Novel compounds, compositions and therapeutic uses thereof

Abstract

The present invention relates to compounds of the Formula (I), and pharmaceutically salts thereof: wherein integer a, X1, X2, X3, X4, RN and RA are each as defined herein. The compounds of the present invention inhibit WRN. The novel therapeutic compounds are therefore useful for the treatment and / or prevention of diseases and conditions in which WRN activity is implicated, such as, for example but not limited to, the treatment and / or prevention of cancer. The present invention also relates to pharmaceutical compositions comprising the novel therapeutic compounds defined herein, to processes for synthesising these compounds and to their use for the treatment of diseases and / or conditions in which WRN activity is implicated.

Description

NOVEL COMPOUNDS, COMPOSITIONS AND THERAPEUTIC USES THEREOFINTRODUCTION

[0001] The present invention relates to novel therapeutic compounds. More specifically, the present invention relates to novel therapeutic compounds that inhibit Werner syndrome helicase protein (WRN, RECQ3). The novel therapeutic compounds are therefore useful for the treatment and / or prevention of diseases and conditions in which WRN activity is implicated, such as, for example but not limited to, the treatment and / or prevention of cancer. The present invention also relates to pharmaceutical compositions comprising the novel therapeutic compounds defined herein, to processes for synthesising these compounds and to their use for the treatment of diseases and / or conditions in which WRN activity is implicated.BACKGROUND OF THE INVENTION

[0002] Microsatellite instability (MSI) is a genomic abnormality that plays a crucial role in the development and progression of various types of cancer, including endometrial (31.4%), colorectal (15%), gastric (15%) and ovarian cancers (12%) (Boland et al, 2010; Bonneville et al, 2017; zhang et al, 2020). It is characterized by the accumulation of changes in repetitive DNA sequences known as microsatellites.

[0003] The stability of the microsatellite repeats through DNA replication is maintained by a DNA repair mechanism called DNA mismatch repair (MMR) (Aaltonen et al; 1993). Mutation or silencing of MMR genes, including MLH1 , MSH2, MSH6 and PMS2 leads to disruption of microsatellite repeat sequence integrity, through small insertions or deletions. This results in an MSI phenotype, characterized by changes in the length of these repetitive sequences (Li et al, 2020). This phenotype can be assessed through molecular testing of specific microsatellites, or immunohistochemical evaluation of MMR protein expression (van Wietmarschen et al., 2020). One of the key clinical implications of high microsatellite instability (MSI-H), besides its high prevalence in different cancers, lies in its predictive value for response to immunotherapy. However, while checkpoint inhibitors have been shown to lead to longer proliferation free survival than chemotherapy for metastatic MSI-H colorectal cancer (Andre et al 2020), 30-35% of patients still fail to derive any benefit from immune response inhibitors and many other patients develop resistance (Roth et al 2021), indicating a clear clinical need.

[0004] The Werner syndrome helicase protein (RECQ3, WRN) functions as a DNA helicase and exonuclease, unwinding double-stranded DNA structures and resolving secondary DNA structures during replication, damage repair and recombination processes. It therefore plays a crucial role in maintaining the integrity of the genome (Rossi et al., 2010). Deficiencies or dysfunctions in WRN have been associated with genomic instability, accelerated aging and increased susceptibility to cancer development (Crabbe L. et al., 2004). Recently, WRN has been shown by independent groups to be essential in MSI-High tumour cells (Behan et al, 2019; Chan et al 2019). The WRN helicase is required to unwind the secondary DNA structures that form within the abnormally expanded microsatellite repeats, such as hairpin loops and cruciform structures. In the absence of WRN these secondary structures undergo nuclease cleavage resulting in increased DNA double-strand breaks (DSBs), chromosome breakage, mitotic failures and subsequent growth arrest and cell death (van Wietmarschen N. et al., 2020).

[0005] In conclusion, microsatellite instability is a common genomic abnormality in cancerthat arises from defects in the DNA mismatch repair system and targeting the helicase activity of WRN represents a promising therapeutic approach for those MSI-High cancers. Furthermore, the broader implications of WRN's global DNA metabolism activity suggest its potential as a therapeutic target in various cancer contexts.

[0006] There is therefore a need to provide novel therapeutics that can effectively target and inhibit WRN activity.

[0007] The present invention was devised with the foregoing in mind.ReferencesAaltonen L.A. et al. Clues to the pathogenesis of familial colorectal cancer, Science. 1993 May 7;260(5109):812-6.Andre T. et al. Pembrolizumab in M icrosatellite-l nstability-High Advanced Colorectal Cancer, N Engl J Med. 2020 Dec 3;383(23):2207-2218.Behan F.M. et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens, Nature. 2019 Apr;568(7753):511-516Boland C.R. et al. Microsatellite instability in colorectal cancer, Gastroenterology. 2010 Jun;138(6):2073-2087.e3Bonneville R. et al. Landscape of Microsatellite Instability Across 39 Cancer Types, JCO Precis Oncol. 2017; 2017: PO.17.00073Chan M.E. et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature. 2019 Apr; 568(7753): 551-556Crabbe L. et al. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity, Science. 2004 Dec 10;306(5703):1951-3Li K. et al. Microsatellite instability: a review of what the oncologist should know, Cancer Cell Int. 2020 Jan 13;20:16Rossi M.L. et al. Roles of Werner Syndrome Protein in Protection of Genome Integrity, DNA Repair. 2010 Mar 2; 9(3): 331-344.Roth, M.T. et al. Pembrolizumab in unresectable or metastatic MSI-high colorectal cancer: safety and efficacy, Expert Rev Anticancer Ther. 2021 Feb; 21 (2): 229-238.Van Wietmarschen N. et al. Repeat expansions confer WRN dependence in microsatellite- unstable cancers, Nature. 2020 Oct;586(7828):292-298.Zhang C. et al. Incidence and detection of high microsatellite instability in colorectal cancer in a Chinese population: a meta-analysis, J Gastrointest Oncol. 2020; 11(6):1155-1163SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides a compound of Formula I as defined herein, and / or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0009] In another aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0010] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0011] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition in which WRN activity is implicated.

[0012] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein, for use in the treatment of a disease or condition associated with aberrant activity of WRN.

[0013] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer or benign neoplasms.

[0014] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cancer.

[0015] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which WRN activity is implicated.

[0016] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition associated with aberrant activity of WRN.

[0017] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of cancer or benign neoplasms.

[0018] In another aspect, the present invention the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a cancer.

[0019] In another aspect, the present invention provides a method of treating a disease or condition in which WRN activity is implicated, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0020] In another aspect, the present invention provides a method of treating a disease or condition associated with aberrant activity of WRN, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0021] In another aspect, the present invention provides a method of treating cancer or benign neoplasms, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0022] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0023] In another aspect, the present invention provides a combination treatment comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, with one or more additional therapeutic agents.

[0024] In another aspect, the present invention provides processes for preparing compounds of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, with one or more additional therapeutic agents.

[0025] In a further aspect, the present invention provides the use of a compound of Formula I or a salt, hydrate or solvate thereof, for CRISPR gene editing in vitro or in vivo.

[0026] In another aspect, the present invention provides the use of a compound of Formula I or a salt, hydrate or solvate thereof, for increasing the efficiency of CRISPR gene editing in vitro or in vivo.

[0027] In another aspect, the present invention provides a compound of Formula I, or a salt, hydrate or solvate thereof, for use in CRISPR gene editing in vivo.

[0028] In another aspect, the present invention provides a compound of Formula I, or a salt, hydrate or solvate thereof, for use in increasing the efficiency of CRISPR gene editing in vivo.

[0029] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0030] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0031] It is to be appreciated that references to “treating” or “treatment” include prophylaxisas well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0032] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0033] References to “WRN” refer to Werner syndrome helicase protein (WRN, RECQ3).

[0034] The compounds and intermediates described herein may be named according to either the IIIPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, the terms “compounds of Formula I”, “compounds of the invention” and the more general term “compounds” refer to and include any and all compounds described by and / or with reference to Formula I herein. It should also be understood that these terms encompasses all stereoisomers, i.e. cis and trans isomers, as well as optical isomers, i.e. R and S enantiomers, of such compounds, in substantially pure form and / or any mixtures of the foregoing in any ratio. This understanding extends to pharmaceutical compositions and methods of treatment that employ or comprise one or more compounds of the Formula I , either by themselves or in combination with additional agents.

[0035] Unless specified otherwise, atoms are referred to herein by their chemical symbol as appearing in the IUPAC periodic table of the Elements. For example, “C” refers to a carbon atom.

[0036] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0037] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For Example, “(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example “phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0038] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2- methylpropylene, pentylene, and the like.

[0039] “(3-6C)cycloalkyl” means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0040] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

[0041] As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Representative examples include, but are not limited to, -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, and -CH2CF3. Suitably, a haloalkyl group is selected from -CHF2 and -CF3, suitably -CF3.

[0042] As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Representative examples include, but are not limited to, -OCF3, -OCHF2, -OCH2F, and -OCF2CF3. Suitably, a haloalkyoxy group is selected from -OCHF2 and -OCF3, suitably -OCF3.

[0043] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as, but not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2 / 7-thiopyran, and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl,tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as, but not limited to, tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6- dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0044] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0045] By “spiro bicyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0046] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 14, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0047] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-ooxazinyl-,1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2, 1 b]thiazoly I , -imidazo[1 , 2b] [ 1 , 2 , 4]-triazi ny I . “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a nonaromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or -sulfur-. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl,1.2.3.4-tetrahydro-1 ,8-naphthyridinyl, 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl,3.4-dihydro-2 / 7-pyrido[3,2-b][1 ,4]oxazinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrazinyl.

[0048] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0049] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0050] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.

[0051] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0052] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0053] The term “aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0054] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.

[0055] The term “aryl(1-2C)alkyl” means an aryl group covalently attached to a (1-2C)alkylene group, both of which are defined herein. Examples of aryl-(1-2C)alkyl groups include benzyl, phenylethyl, and the like.

[0056] “Heteroaryl(1-3C)alkyl” means a heteroaryl group covalently attached to a (1- 3C)alkylene group, both of which are defined herein. Examples of heteroaryl-alkyl groups include pyridin-3-ylmethyl, 2-(benzofuran-2-yl)ethyl, and the like.

[0057] “Heterocyclyl(1-2C)alkyl” means a heterocyclyl group covalently attached to a (1- 2C)alkylene group, both of which are defined herein.

[0058] “(3-6C)cycloalkyl-(1-2C)alkyl” means a (3-6C)cycloalkyl group covalently attached to a (1-2C)alkylene group, both of which are defined herein.

[0059] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term “wherein a / any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R1group is substituted by a relevant stipulated group.

[0060] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0061] A wavy bond (J^ ) is used herein to show a point of attachment.

[0062] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

[0063] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and / or physically compatible with other ingredients (such as, for example, with reference to a formulation), and / or are generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

[0064] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, suitably refer to mammals, in particular humans.Compounds of the invention

[0065] In a first aspect, the present invention relates to a compound, or pharmaceutically acceptable salt thereof, having the structural formula I shown below:wherein: integer a is 1 or 2;Xi is selected from N or CRi;X2 is selected from N or CR2;X3 is selected from N or CR3;X4 is selected from N or CR4; wherein:R1 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2;R2 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2;R3 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2;R4 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2; with the proviso that:(i) up to three of Xi, X2, X3 and X4 can be N; and(ii) up to three of R1, R2, R3 and R4 can be a substituent other than hydrogen;RN is hydrogen or RN and R1 are linked to form a fused 5 or 6-membered heterocyclic ring;RA is selected from halo, cyano, or a group:-LA-XA-QAwherein:LAis absent or (1-4C)alkylene, (2-4C)alkenylene or (2-4C)alkynylene;XAis absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(0)o-2-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, -NR100a-,-N(R100a)-C(O)-NR100a-, -SO2N(R100a)- or-N(R100a)SO2-, where each R100agroup present is independently selected from hydrogen or (1 -2C)alkyl; andQAis selected from the group consisting of hydrogen, or a (1 -6C)alkyl, -[CH2]n- (3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-aryl group -[CH2]n- heteroaryl group, wherein integer n is 0, 1 , 2, 3 or 4; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-3C)alkyl, (1- 3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of Xi, X2, X3 and X4 are CH.

[0066] Suitably, only one or two of Xi, X2, X3 and X4 can be N.

[0067] Suitably, only one or two of R1, R2, R3 and R4can be a substituent other than hydrogen. More suitably, only one of R1, R2, R3 and R4 can be a substituent other than hydrogen.

[0068] Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of integer a, Xi, X2, X3, X4, RA and RN each have any of the meanings defined hereinbefore, or are as defined in any one of paragraphs (1) to (XX) hereinafter:(1) integer a is 1 ;(2) integer a is 2;(3) Xi is selected from N or CR1;X2is selected from N or CR2;X3 is selected from N or CR3;X4 is selected from N or CR4; wherein:R1 is selected from hydrogen, halo, methyl, methoxy or NH2;R2is selected from hydrogen, halo, methyl, methoxy or NH2;Rs is selected from hydrogen, halo, methyl, methoxy or NH2;R4 is selected from hydrogen, halo, methyl, methoxy or NH2; with the proviso that: up to two of Xi, X2, X3 and X4 can be N; and up to two of R1, R2, R3 and R4 can be a substituent other than hydrogen;(4) Xi is selected from N or CR1;X2 is selected from N or CR2;X3 is selected from N or CR3;X4 is selected from N or CR4; wherein:R1 is selected from hydrogen, methyl, methoxy or NH2;R2 is selected from hydrogen, methyl, methoxy or NH2;R3 is selected from hydrogen, methyl, methoxy or NH2;R4 is selected from hydrogen, methyl, methoxy or NH2; with the proviso that: up to two of Xi, X2, X3 and X4 can be N; and up to two of R1, R2, R3 and R4 can be a substituent other than hydrogen;(5) Xi is selected from N or CR1;X2 is selected from N or CR2;X3 is selected from N or CR3;X4 is selected from N or CR4; wherein:R1 is selected from hydrogen, methyl, methoxy or NH2;R2 is selected from hydrogen, methyl, methoxy or NH2;R3 is selected from hydrogen, methyl, methoxy or NH2;R4 is selected from hydrogen, methyl, methoxy or NH2; with the proviso that:up to two of Xi, X2, X3 and X4 can be N; and only one of R1, R2, R3 and R4 can be a substituent other than hydrogen;(6) Xi is selected from N or CR1;X2 is selected from N or CR2;X3 is selected from N or CR3;X4 is selected from N or CR4; wherein:R1 is selected from hydrogen or methoxy or NH2;R2 is hydrogen;R3 is selected from hydrogen or methyl;R4 is selected from hydrogen or NH2; with the proviso that: up to two of Xi, X2, X3 and X4 can be N; and only one of R1, R2, R3 and R4 can be a substituent other than hydrogen;(7) Xi is CH;X2is CH;X3 is CH; andX4is CH;(8) Xi is N;X2is CH;X3 is CH; andX4is CH;(9) Xi is CH;X2is CH;X3 is C-CH3; andX4is CH;(10) Xi is C-OCH3;X2is N; X3is CH; and X4 is CH; (11) X1is CH; X2is CH; X3is N; and X4is CH; (12) X1is CH; X2is N; X3is CH; and X4is CH; (13) X1is CH; X2is CF; X3is CH; and X4is CH; (14) X1is N; X2is N; X3 is CH; and X4 is CH; (15) X1 is CH; X2 is N; X3 is CH; and X4 is N; (16) RN is hydrogen or RN and R1 are linked to form a fused 6-membered heterocyclic ring; (17) RN is hydrogen or RN and R1 are linked to form a -CH2-CH2- or -CH=CH- group; (18) RN and R1 are linked to form a -CH2-CH2- or -CH=CH- group; (19) RA is selected from halo, cyano, or a group:-LA-XA-QAwherein: LAis absent or (1-3C)alkylene, (2-3C)alkenylene or (2-3C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)0-2-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, -NR100a-, -N(R100a)-C(O)-NR100a-, -SO2N(R100a)- or -N(R100a)SO2-, where each R100agroup present is independently selected from hydrogen or (1-2C)alkyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, -[CH2]n- (3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-aryl group -[CH2]n- heteroaryl group, wherein integer n is 0, 1, 2, 3 or 4; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH; (20) RAis selected from halo, cyano, or a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene, (2-3C)alkenylene or (2-3C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)0-2-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, -NR100a-, -SO2N(R100a)- or -N(R100a)SO2-, where each R100agroup present is independently selected from hydrogen or methyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, -[CH2]n- (3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-phenyl group -[CH2]n- heteroaryl group, wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH; (21) RA is selected from halo, cyano, or a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene or (2-3C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, or -NR100a-, where each R100agroup present is independently selected from hydrogen or methyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, -[CH2]n- (3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-phenyl group -[CH2]n- heteroaryl group, wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl or (1- 2C)alkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3 and X4 are CH; (22) RA is a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene or (2-3C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, or -NR100a-, where R100ais selected from hydrogen or methyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, (3- 6C)cycloalkyl, heterocyclyl group, phenyl group or heteroaryl group, wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl or (1- 2C)alkoxy;and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH; (23) RA is a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene or (2-3C)alkynylene; XAis absent or is selected from -O- or -NR100a-, where R100ais selected from hydrogen or methyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, (3- 6C)cycloalkyl, heterocyclyl group, phenyl group or heteroaryl group, wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl or (1- 2C)alkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH; (24) RAis a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene or (2-3C)alkynylene; XAis absent or is selected from -O- or -NR100a-, where R100ais selected from hydrogen or methyl; and QAis selected from (1-6C)alkyl, (3-6C)cycloalkyl or phenyl; wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, yl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl or (1- 2C)alkoxy; (25) RA is selected from:with the proviso RA is not phenyl when all of X1, X2, X3 and X4 are CH;

[0069] Suitably, in the compounds of formula I, integer a is 1.

[0070] Suitably, in the compounds of formula I, X1, X2, X3 and X4 are as defined hereinbefore or are as defined in any one of paragraphs (3) to (15) above. More suitably, X1, X2, X3 and X4 are as defined in paragraph (6) above. Most suitably, X1, X2, X3 and X4 are as defined in any one of paragraphs (7) to (15) above.

[0071] Suitably, in the compounds of formula I, X1, X2, X3 and X4 are as defined hereinbefore or are as defined in any one of paragraphs (3) to (15) above and RN is as defined in paragraph (17) or (18). More suitably, X1, X2, X3 and X4 are as defined in paragraph (6) above and RN is as defined in paragraph (17) or (18). Most suitably, X1, X2, X3 and X4 are as defined in any one of paragraphs (7) to (15) above and RN is as defined in paragraph (17) or (18).

[0072] Suitably, in the compounds of formula I, RA is as defined hereinbefore or is as defined in any one of paragraphs (19) to (25) above. More suitably, RA is as defined in paragraphs (21) to (25) above. Most suitably, R1 is as defined in paragraphs (22) or paragraph (23) above.

[0073] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have one of the structural formulae Ia to Iam shown below:wherein: integer a, X1, X2, X3, X4, R1, R2,R3, R4, RNand RAeach have any of the meanings defined hereinbefore, or integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in any one of paragraphs (3) to (15) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (19) to (25) above.

[0074] In a particular group of compounds of the invention, the compounds have the structural formula Ia shown above.

[0075] In a particular group of compounds of the invention, the compounds have the structural formula Ib shown above.

[0076] In a particular group of compounds of the invention, the compounds have the structural formula Ic shown above.

[0077] In a particular group of compounds of the invention, the compounds have the structural formula Id shown above.

[0078] In a particular group of compounds of the invention, the compounds have the structural formula Ie shown above.

[0079] In a particular group of compounds of the invention, the compounds have the structural formula If shown above.

[0080] In a particular group of compounds of the invention, the compounds have the structural formula Ig shown above.

[0081] In a particular group of compounds of the invention, the compounds have the structural formula Ih shown above.

[0082] In a particular group of compounds of the invention, the compounds have the structural formula Ii shown above.

[0083] In a particular group of compounds of the invention, the compounds have the structural formula Ij shown above.

[0084] In a particular group of compounds of the invention, the compounds have the structural formula Ik shown above.

[0085] In a particular group of compounds of the invention, the compounds have the structural formula Im shown above.

[0086] In a particular group of compounds of the invention, the compounds have the structural formula In shown above.

[0087] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (3) above; RN is as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (19) above.

[0088] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (4) above; RN is as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (20) above.

[0089] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present:integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (5) above; RN is as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (20) above.

[0090] A particular group of compounds have any one of the formulae Ia toabove, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (6) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (21) above.

[0091] A particular group of compounds have any one of the formulae Ia toabove, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (7) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (22) above.

[0092] A particular group of compounds have any one of the formulae Ia toabove, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (8) above; RN is as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (22) above.

[0093] A particular group of compounds have any one of the formulae Ia toabove, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (9) above; RN is as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (23) above.

[0094] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (10) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (23) above.

[0095] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (11) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (23) above.

[0096] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (12) above; RNis as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (23) above.

[0097] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (13) above; RN is as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (23) above.

[0098] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (14) above;RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (23) above.

[0099] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (15) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (23) above.

[0100] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2,R3, and R4are as defined in paragraph (15) above; RNis as defined in paragraph (17) or (18) above; and RAis as defined in any one of paragraphs (24) above.

[0101] A particular group of compounds have any one of the formulae Ia to In above, wherein, and where present: integer a is as defined in paragraph (1) or (2) above; X1, X2, X3, X4, R1, R2, R3, and R4 are as defined in paragraph (15) above; RN is as defined in paragraph (17) or (18) above; and RA is as defined in any one of paragraphs (24) above.

[0102] Particular compounds of the present invention include any of the compounds described in the example section of the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following: 4-cyclohexyl-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)benzamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methyl-[1,1'-biphenyl]-4-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methoxy-6-phenylpyridine-3-carboxamide; 3-[6-(cyclopentyloxy)-1-oxo-1,2-dihydro-2,7-naphthyridin-2-yl]-2,3-dihydro-1λ⁶-thiophene-1,1- dione; 3-[6-(cyclopentyloxy)-1-oxo-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]-2,3-dihydro-1λ⁶- thiophene-1,1-dione;N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(2-phenylethynyl)pyridine-3-carboxamide; 6-(cyclopentylamino)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; 4-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)benzamide; 4-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-3-fluorobenzamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridazine-3-carboxamide; 5-(cyclopentyloxy)-N-[(3S)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyrazine-2-carboxamide; 5-cyclobutoxy-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1s,3s)-3-fluorocyclobutoxy]pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1,1,1-trifluoropropan-2-yl)oxy]pyrazine-2- carboxamide; rac-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1R,2R)-2-methylcyclobutoxy]pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1r,3r)-3-fluorocyclobutoxy]pyrazine-2- carboxamide; 5-(3,3-difluorocyclobutoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(2-methylcyclopentyl)oxy]pyrazine-2- carboxamide; 5-[(3,3-difluorocyclopentyl)oxy]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-(propan-2-yloxy)pyrazine-2-carboxamide; 5-{bicyclo[2.2.1]heptan-2-yloxy}-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; 5-(cyclohexyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-[(2,2-difluorocyclopentyl)oxy]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; rac-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1R,2S)-2-methylcyclobutoxy]pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(4,4,4-trifluorobutan-2-yl)oxy]pyrazine-2- carboxamide; 5-[(1,1-difluoropropan-2-yl)oxy]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide;5-(2,2-difluoropropoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-(cyclopentyloxy)-N-[(3R)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide; 5-cyclopropoxy-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-({6,6-difluorobicyclo[3.1.0]hexan-3-yl}oxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[3-(trifluoromethyl)cyclobutoxy]pyrazine-2- carboxamide; 5-cyclobutoxy-N-[(4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-yl]pyrazine-2-carboxamide; 5-cyclobutoxy-N-[(4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-yl]pyrazine-2- carboxamide;3-amino-5-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)pyrazine-2-carboxamide; 6-(cyclopentyloxy)-N-[(3S)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyridine-3-carboxamide; 6-(3-cyclopentylpropoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; 6-(2-cyclopentylethoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; 6-(cyclopentylmethoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(trifluoromethoxy)pyridine-3-carboxamide; 6-(cyclopentyloxy)-N-[(3R)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyridine-3-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-ethoxypyridine-3-carboxamide; 5-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-2-carboxamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-methylpyridine-3- carboxamide; 5-chloro-6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3- carboxamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methylpyridine-3- carboxamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-4-methylpyridine-3- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(3-methylcyclopentyl)oxy]pyrazine-2- carboxamide; or a pharmaceutically acceptable salt thereof.

[0103] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features, or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitablefeatures or particular embodiments.

[0104] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein. Salts and Solvates

[0105] The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and / or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.

[0106] Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and / or physically compatible with the other ingredients comprising a formulation, and / or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

[0107] In one embodiment, the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.

[0108] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. -In addition a suitable pharmaceutically acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable- cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0109] In general, salts of the present application can be prepared in situ during the isolation and / or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and / or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange / double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and / or isolated using a single method or a combination of methods.

[0110] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as, but not limited to, sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

[0111] Certain compounds of the Formula I and sub-formulae thereof may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess the biological activity described herein.Polymorphs

[0112] It is also to be understood that certain compounds of the Formula I and sub-formulae thereof may exhibit polymorphism, and that the invention encompasses all such forms that possess the biological activity described herein. N-oxides

[0113] Compounds of the Formula I and sub-formulae thereof containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I and sub-formulae thereof that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as, but not limited to, hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as, but not limited to, dichloromethane. Tautomers

[0114] Compounds of the Formula I and sub-formulae thereof may exist in a number of different tautomeric forms and references to compounds of the Formula I and sub-formulae thereof include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I and sub-formulae thereof. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), pyrimidone / hydroxypyrimidine, imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolateIsomers

[0115] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are nonsuperimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and Ssequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (- )isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0116] Certain compounds of Formula I and sub-formulae thereof may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and / or isolated as mixtures of enantiomers and / or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and / or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios. Isotopes

[0117] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of12C,13C, and14C; hydrogen atoms may be present in any ratio of1H,2H, and3H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms. Prodrugs and Metabolites

[0118] The compounds of Formula I and sub-formulae thereof may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compoundof the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property- modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I and sub-formulae thereof.

[0119] Accordingly, the present invention includes those compounds of the Formula I and sub-formulae thereof as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I and sub-formulae thereof may be a synthetically-produced compound or a metabolically-produced compound.

[0120] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0121] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; andh) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0122] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as, but not limited to, methyl, ethyl and tert- butyl, C1-6alkoxymethyl esters such as, but not limited to, methoxymethyl esters, C1-6alkanoyloxymethyl esters such as, but not limited to, pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as, but not limited to, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3- dioxolenylmethyl esters such as, but not limited to, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as, but not limited to, methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0123] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula I and sub-formulae thereof containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as, but not limited to, phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as, but not limited to, acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- 10alkoxycarbonyl groups such as, but not limited to, ethoxycarbonyl, N,N –(C1-6)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as, but not limited to, acetoxymethyl and pivaloyloxymethyl groups.

[0124] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as, but not limitedto, ammonia, a C1-4alkylamine such as, but not limited to, methylamine, a (C1-4alkyl)2amine such as, but not limited to, dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-4alkoxy- C2-4alkylamine such as, but not limited to, 2-methoxyethylamine, a phenyl-C1-4alkylamine such as, but not limited to, benzylamine and amino acids such as, but not limited to, glycine or an ester thereof.

[0125] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as, but not limited to, an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-4alkyl)piperazin-1-ylmethyl.

[0126] The in vivo effects of a compound of the Formula I and sub-formulae thereof may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I and sub-formulae thereof. As stated hereinbefore, the in vivo effects of a compound of the Formula I and sub-formulae thereof may also be exerted by way of metabolism of a precursor compound (a pro-drug). Pharmaceutical Compositions

[0127] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0128] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0129] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0130] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0131] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 1.5 g of active agent (more suitably from 0.5 to 600 mg, for example from 1 to 200 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0132] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0133] It is to be noted that dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present application encompasses intra- patient dose-escalation as determined by the person skilled in the art. Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan. As such, one of ordinary skill would readily appreciate and recognize that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

[0134] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used.

[0135] For the compounds of the present invention, oral administration is particularly suitable. The compounds of the present invention may be formulated as a tablet, capsule or solution for oral administration. Suitably, the compound of the present invention is formulated in a unit dosage form (e.g. a tablet or capsule) for oral administration. Typically, unit dosage forms will contain about 0.5 mg to 1.5 g of a compound of this invention. Synthesis

[0136] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular methods for forming compounds of formula I defined herein are shown in the accompanying example section.

[0137] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0138] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0139] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0140] For Examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described inthe literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0141] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0142] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as, but not limited to, acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tbutoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as, but not limited to, an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tertbutoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0143] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0144] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroaceticacid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0145] Resins may also be used as a protecting group.

[0146] The methodology employed to synthesise a compound of formula (I) will vary depending on the nature of ring A, R1, R100, R2, R3, integer a, integer b, X4, X5, X6, X7, Rx4, Rx5, Rx6, Rx7,X8, R100aand R100band any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying example section.

[0147] Once a compound of formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise one or more of the additional steps of: (i) removing any residual protecting groups present; (ii) converting the compound formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula I; and / or (iv) forming a prodrug of the compound of formula I.

[0148] An example of (ii) above is when a compound of formula (I) is synthesised and then one or more of the groups of ring A, R1, R100, R2, R3, integer a, integer b, X4, X5, X6, X7, Rx4, Rx5, Rx6, Rx7, X8, R100a and R100b may be further reacted to change the nature of the group and provide an alternative compound of formula (I).

[0149] The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art. Therapeutic Uses and Applications

[0150] The compounds of the present invention are inhibitors of WRN activity. Data showing the WRN inhibition for the exemplified compounds is presented in the accompanying example section.

[0151] Accordingly, the compounds of formula I are useful for the treatment and / or prevention of diseases and conditions in which WRN activity is implicated, such as, for example, but not limited to, the treatment and / or prevention of cancer and / or benign neoplasms.

[0152] In one aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0153] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition in which WRN activity is implicated.

[0154] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which WRN activity is implicated.

[0155] In another aspect, the present invention provides a method of treating a disease or condition in which WRN activity is implicated, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0156] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition associated with aberrant activity of WRN.

[0157] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition associated with aberrant activity of WRN.

[0158] In another aspect, the present invention provides a method of treating a disease or condition associated with aberrant activity of WRN, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0159] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer or benign neoplasms.

[0160] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of cancer or benign neoplasms.

[0161] In another aspect, the present invention provides a method of treating a cancer or a benign neoplasm, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0162] A benign neoplasm may be, for example, hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, pyogenic granulomas, moles, uterine fibroids, thyroid adenomas, adrenocortical adenomas or pituitary adenomas. The benign neoplasm may be endometrial implants or a keratocystic odontogenic tumor.

[0163] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cancer.

[0164] In another aspect, the present invention the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a cancer.

[0165] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0166] In another aspect, the present invention provides a method for treating a cancer having microsatellite instability (MSI), the method comprises administering a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. In some embodiments, the cancer cells are characterized as having MSI low (MSI-L). In some embodiments, cancer cells characterized as having high MSI (MSI-H), used interchangeably with MSI-high. Cells can be characterized as MSI, including MSI-L or MSI-H, or as MSS (MS-stable), according to methods known in the art (see, for example, Dudley, Jonathan C., et al., Clinical Cancer Research, 22(4): 813-820, 2016.). MSI-H is used to classify tumors as having a high frequency of MSI.A tumor can be classified as MSI, including MSI-low or MSI-high, using polymerase chain reaction (PCR) and / or immunohistochemistry (IHC) assays. As stated in Dudley et al., a tumor is classified as MSI-H by PCR if (i) there is a shift (usually downward) in the size of at least two microsatellite loci from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel,” also referred to herein as the “NCI-Reference Panel (Bethesda, 1998)”, which includes two mononucleotide loci (BAT-25 and BAT-26) and three dinucleotide loci (D2S123, D5S346, and D17S250), or alternatively, the reference panel can be Promega Corporation’s MSI Analysis System, which includes five mononucleotide loci (BAT-25, BAT-26, NR-21, NR-24, and MONO-27); or (ii) there is a shift in the size of 30% or more microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal. The MSI-H phenotype is associated with germline defects in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, and is the primary phenotype observed in tumors from patients with HNPCC / Lynch syndrome. A tumor is classified as MSI-H in IHC test if it shows a loss of protein expression for at least 1 of the above 4 mismatch repair genes. Cells can be similarly classified as MSI-H using the tests described herein for tumors.

[0167] In some embodiments, a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of the “Bethesda Panel” (BAT-25, BAT-26, D2S123, D5S346, and D17S250) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.

[0168] In some embodiments, a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of Promega Corporation’s MSI Analysis System (BAT-25, BAT-26, NR- 21, NR-24, and MONO-27) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.

[0169] In some embodiments, a tumor is classified as MSI-H using IHC to determine the expression level of the MMR proteins MLH1, MSH2, MSH6, and / or PMS2 in both tumor tissue and normal tissue, wherein the tumor is classified as MSI-H if there is a loss of protein expression for at least one of the MMR proteins in the tumor tissue relative to the normal tissue. In some embodiments, the loss of protein expression is a decrease of at least 20% (such as a decrease of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more).

[0170] In contrast, a tumor is classified as MSI-L by PCR if (i) there is a shift in the size of one microsatellite locus from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel” or Promega Corporation’s MSI Analysis System; or (ii) there is a shift in the size of less than 30% microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal. MSI- L tumors are thought to represent a distinct mutator phenotype with potentially different molecular etiology than MSI-H tumors (Thibodeau, 1998; Wu et al., 1999, Am J Hum Genetics 65: 1291-1298). Cells can be similarly classified as MSI-L using the tests described herein for tumors.

[0171] Cancers classified as MSI-H include, but not limited to, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adenoid cystic carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, and endocervical adenocarcinoma.

[0172] In one embodiment, wherein the cancer is treatable by inhibition of WRN. In one embodiment, the cancer is characterized by MSI-H and / or dMMR.

[0173] The cancer may be non-metastatic or metastatic and which may be a solid tumour or a haematological (“liquid”) cancer. The cancer may, for example, be selected from: (1) Carcinoma, including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet ring cell carcinoma, bladder carcinoma (including transitional cell carcinoma (a malignant neoplasm of the bladder)), bronchogenic carcinoma, colorectal carcinoma (including, but not limited to, colon carcinoma and rectal carcinoma), anal carcinoma, gastric carcinoma, lung carcinoma (including but not limited to small cell carcinoma (SCLC) and non-small cell carcinoma of the lung (NSCLC), lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mesothelioma), neuroendocrine tumors (including but not limited to carcinoids of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma (including, but not limited to, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous neoplasm with invasive carcinoma, mucinous cystic neoplasm with invasive carcinoma, islet cell carcinoma and neuroendocrinetumors), breast carcinoma (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma), ovarian carcinoma (including, but not limited to, ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex-cord- stromal tumor), liver and bile duct carcinoma (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate carcinoma, adenocarcinoma, brain tumours (including, but not limited to glioma, glioblastoma and medulloblastoma), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney carcinoma (including, but not limited to, renal cell carcinoma, clear cell carcinoma and Wilm's tumor), medullary carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical carcinoma, uterine carcinoma (including, but not limited to, endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors), testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and oropharyngeal squamous carcinoma; (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective tissue types) and other soft tissue sarcomas; (3) Myeloma and multiple myeloma; (4) Hematopoietic tumours, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis. (5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas;(6) Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma; (7) Melanoma, uveal melanoma and retinoblastoma; and (8) Mixed Types, including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.

[0174] Further examples of cancers (and their benign counterparts) which may be treated (or inhibited) include, but are not limited to tumours of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney, lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (for example thyroid follicular carcinoma), adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e. leukemias, lymphomas) and premalignant haematological disorders and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (for example acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, MALT lymphoma, T-cell lymphomas and leukaemias, natural killer [NK] cell lymphomas, Hodgkin’s lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumours of mesenchymal origin, for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas,leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi’s sarcoma, Ewing’s sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumours of the central or peripheral nervous system (for example astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas); endocrine tumours (for example pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid); ocular and adnexal tumours (for example retinoblastoma); germ cell and trophoblastic tumours (for example teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and paediatric and embryonal tumours (for example medulloblastoma, neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).

[0175] Particular examples of cancers that can be targeted with the compounds of the present invention include, but are not limited to lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, prostate cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer. More particularly, the cancers may be one or more of the following breast cancer, ovary cancer, pancreatic cancer, prostate cancer, lung cancer and / or colorectal cancer.

[0176] Many diseases are characterized by persistent and unregulated angiogenesis. Chronic proliferative diseases are often accompanied by profound angiogenesis, which can contribute to or maintain an inflammatory and / or proliferative state, or which leads to tissue destruction through the invasive proliferation of blood vessels. Tumour growth and metastasis have been found to be angiogenesis-dependent. Compounds of the invention may therefore be useful in preventing and disrupting initiation of tumour angiogenesis. In particular, the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers.

[0177] Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. The cancers which can be treated by the compounds of the invention include primary tumours (i.e. cancer cells at the originating site), local invasion (cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumours ie. tumours that have formed frommalignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body.

[0178] Particular cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.

[0179] The compounds may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitising cells to chemotherapy and as an anti-metastatic agent. Routes of Administration

[0180] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0181] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (e.g. by a patch, plaster, etc.); transmucosal (e.g. by a patch, plaster, etc.); intranasal (e.g. by nasal spray); ocular (e.g. by eye drops, eye ointment etc.); pulmonary (e.g. by inhalation or insufflation therapy, for example via an aerosol, for example by the nose or mouth); rectal (e.g. by suppository or enema); vaginal (e.g. by pessary); parental, for example by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir dosage form, for example subcutaneously or intramuscularly.

[0182] The compounds of the present invention are particularly suitable for oral administration. Combination Therapies

[0183] The compounds of the invention and salts, solvates thereof defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, one or more additional therapeutic agents, e.g. an anti-tumour agent.

[0184] In the context of cancer treatment, in addition to the compound of the invention, therapy may additionally involve conventional surgery, radiotherapy and / or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-- other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as, but not limited to, alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as, but not limited to, fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, irinotecan, topotecan and camptothecin); - cytostatic agents such as, but not limited to, antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5^-reductase such as, but not limited to, finasteride; - anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; - inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as, but not limited to, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib,OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin- 4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as, but not limited to, lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as, but not limited to, imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as, but not limited to, farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as, but not limited to, CDK2 and / or CDK4 inhibitors; - antiangiogenic agents such as, but not limited to, those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as, but not limited to, vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6- methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00 / 47212), compounds such as, but not limited to, those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ^v^3 function and angiostatin)]; - vascular damaging agents such as, but not limited to, Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; - an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; - antisense therapies, for example those which are directed to the targets listed above, such as, but not limited to, ISIS 2503, an anti-ras antisense; - gene therapy approaches, including for example approaches to replace aberrant genes such as, but not limited to, aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as, but not limited to, those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approachesto increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and - immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as, but not limited to, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as, but not limited to, cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

[0185] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.

[0186] In a further embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, standard chemotherapy for the cancer concerned and / or therapy with DNA damage repair inhibitors (e.g. PARP, ATM, ATR, WEE1, CHK1, POLQ, USP1 and DNAPK inhibitors).

[0187] In a further embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, therapy with a PARP inhibitor.

[0188] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0189] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

[0190] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as, but not limited to, cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.

[0191] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in thetreatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0192] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. In one embodiment, a combination refers to a combination product.

[0193] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier. Combination therapy with immune checkpoint inhibitors

[0194] Immune checkpoint proteins present on immune cells and / or cancer cells [e.g. CTLA4 (also known as cytotoxic T-lymphocyte-associated protein 4 and CD152), LAG3 (also known as lymphocyte-activation gene 3 and CD223), PD1 (also known as programmed cell death protein 1 and CD279), PD-L1 (also known as programmed death-ligand 1 and CD274), TIM- 3 (also known as T-cell immunoglobulin mucin-3) and TIGIT (also known as T-cell Immunoreceptor with Ig and ITIM domains) are molecular targets that have been found to play an important role in regulating anti-tumour immune responses. Inhibitors of these immune checkpoint proteins (e.g. CTLA4, LAG3, PD1, PD-L1, TIM-3 and / or TIGIT inhibitors) promote an anti-tumour immune response that can be utilised to effectively treat certain forms of cancer.

[0195] In one aspect, the present invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0196] In another aspect, the present invention relates to a use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immunecheckpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating of a proliferative disorder.

[0197] In another aspect, the present invention relates to a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0198] Suitably, the compound as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneous, separate or sequential administeration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0199] Any immune checkpoint inhibitor or immune stimulator may be used in the combination therapy defined herein.

[0200] In one embodiment, the immune stimulator is selected from a 4-1BB stimulator, a OX40 stimulator, a CD27 stimulator, a CD40 stimulator, and a DR3 stimulator. In another embodiment the immune checkpoint inhibitor is selected from a PD1-inhibitor, a PD-L1 inhibitor, a LAG3 inhibitor, CTLA-4 inhibitor, a TIM-3 inhibitor and / or a TIGIT inhibitor. In a particular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[0201] PD-1 is a cell surface receptor protein present on immune cells such as T cells. PD- 1 plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell activation. The PD-1 protein is an immune checkpoint that guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells).

[0202] PD-1 therefore inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

[0203] PD1 binds two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest as it is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 that boost the immune system are approved or are being developed for the treatment of cancer. Many tumour cells express PD- L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumour activity. This is known as immune checkpoint blockade.

[0204] Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics) and MEDI-0680 (MedImmune).

[0205] Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use against other types of cancer.

[0206] Examples of LAG3 inhibitors include BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781 and LAG525.

[0207] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN1884, and CP- 675,206 / Tremelimumab. Biological Activity

[0208] The biological assay described in the example section (Biological Assay 1) may be used to measure the pharmacological effects of the compounds of the present invention.

[0209] Although the pharmacological properties of the compounds of formula I vary with structural change, as expected, the compounds of the invention were found to be active in the assays described in Biological Assay 1. In general, the compounds of the invention demonstrate an IC50 of 100^M or less in the assay described in Biological Assay 1, with preferred compounds of the invention demonstrating an IC50 of 50^M or less and the most preferred compounds of the invention demonstrating an IC50of 10^M or less. EXAMPLES

[0210] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named using conventional IUPAC nomenclature, or as named by the chemical supplier.

[0211] The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesized according to the step in the description given. Experimental and instrumentation

[0212] All solvents, chemical reagents and starting materials were obtained from commercial sources and were used without further purification or drying. NMR spectra were recorded using either a Bruker Avance III HD 500 MHz NMR spectrometer or a Bruker Avance III HD 400 MHz NMR spectrometer as indicated. Chemical shifts are quoted in ppm using residual undeuterated solvent as the internal reference.

[0213] LCMS spectra were recorded on a Waters AQUITYTMUPLCTMusing either METHOD A; Waters UPLCTMBEHTMC18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.9 mL / min and a gradient of 5 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile, METHOD B; Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile, METHOD C; Waters UPLCTMBEHTMC18 column (2.1 mm × 30 mm, 1.7 µm; temperature 55 °C), with an injection volume of 1 µL at a flow rate of 1.0 mL / min and a gradient of 1 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile, or METHOD D; Waters UPLCTMBEHTMC18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 55 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile.. Mass spectra were obtained using a Waters SQD, SQD2 or a QDA detector using electrospray ionisation in positive or negative mode. UV purity was assigned using AUC monitoring at 215, 254 or 280 nm. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0214] Preparative HPLC was performed using either METHOD 1; Waters SunfireTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 1.90 min then a gradient of 30 – 95% B over 9.60 min and held for 1.97 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile, METHOD 2; Waters XBridgeTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40mL / min at 30% B for 2.00 min then a gradient of 30 – 95% B over 9.50 min and held for 1.97 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile, METHOD 3; Waters SunfireTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10 – 95% B over 14.10 min and held for 2.0 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile, or METHOD 4; Waters XBridgeTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 2.00 min then a gradient of 10 – 95% B over 14.00 min and held for 2.00 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. UV spectra were recorded at 215 nm using a Gilson detector.

[0215] Column chromatography was typically undertaken with a Biotage®Selekt automated purification system, employing pre-packed Sfär Silica D Duo 60 µm or Sfär Silica 60 µm cartridges of an appropriate size. Specific solvent gradients used are specified.

[0216] Unless otherwise specified, all lyophilisation was from MeCN / water mixtures. List of Abbreviations RT Room Temperature THF Tetrahydrofuran DCM Dichloromethane DIPEA N,N-diisopropylethylamine DMF Dimethylformamide Sat. Saturated HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate TBME tert-butyl methyl ether T3P tripropyl-1,3,5,2λ⁵,4λ⁵,6λ⁵-trioxatriphosphinane-2,4,6-trione CMBP (Tributylphosphoranylidene)acetonitrile HPLC High-performance liquid chromatography IPA iso-propyl alcohol KHMDS Potassium bis(trimethylsilyl)amide NMP N-methyl pyrrolidinone rt Retention time LCMS Liquid chromatography mass spectrometry DMSO Dimethyl sulfoxide MW Microwave app. ApparentScheme 1 synthesis of examples in one synthetic step via amide couplingExamples prepared in accordance with Scheme 1 Example X5 N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-phenylpyridine-2- carboxamideHATU (115 mg, 0.304 mmol) was added to a stirred solution of 5-phenylpyridine-2-carboxylic acid (60 mg, 0.289 mmol), 3-amino-2,3-dihydro-1λ⁶-thiophene-1,1-dione hydrochloride (54 mg, 0.32 mmol) and DIPEA (151 µL, 0.87 mmol) in anhydrous DMF (1 mL) at RT. The resulting mixture was stirred at RT for 2.5 h then mixed with saturated NaHCO3(aq) (5 mL) and the crude product extracted with DCM (15 mL). The organic phase was passed over a hydrophobic phase separator then concentrated in vacuo. Preparative HPLC (Method 4, 215 nm) followed by lyophilisation afforded N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5- phenylpyridine-2-carboxamide (24 mg, 26%) as a colourless solid.1H NMR (500 MHz, DMSO- d6) δ 9.44 (d, J = 8.1 Hz, 1H), 8.96 (dd, J = 2.4, 0.8 Hz, 1H), 8.31 (dd, J = 8.2, 2.3 Hz, 1H), 8.12 (dd, J = 8.2, 0.8 Hz, 1H), 7.85 – 7.78 (m, 2H), 7.59 – 7.53 (m, 2H), 7.51 – 7.45 (m, 1H), 7.22 (dd, J = 6.7, 2.3 Hz, 1H), 6.95 (dd, J = 6.7, 2.4 Hz, 1H), 5.44 – 5.35 (m, 1H), 3.76 (dd, J = 13.4, 7.8 Hz, 1H), 3.44 (dd, J = 13.4, 5.9 Hz, 1H). LCMS: Method B, rt 2.64 min, [M+H]+ m / z 315.1, purity 100%. Some examples were instead purified directly without aqueous work up. These are markedband the isolation procedure was instead in a manner analogous to that outlined below: Variant b: The mixture was diluted with DMSO / MeOH (1:1, approx.1.5 mL) then filtered and purified by preparative HPLC and isolated by lyophilisation. Prepared in a fashion analogous to example X5 were examples shown in table 1 below. Table 1, Examples prepared in one synthetic step via amide coupling with HATU, in accordance with scheme 1.Example X55 - 6-(cyclopentyloxy)-N-[(3S)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl]pyridine-3-carboxamide (ISOMER 1) andExample X62 - 6-(cyclopentyloxy)-N-[(3R)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl]pyridine-3-carboxamide (ISOMER 2)6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide (30 mg) was subjected to chiral preparative chromatography under the following conditions; Column type: Chiralpak AD-H, 20 x 250mm, 5µm, mobile phase: Methanol, Flow rate: 9 mL / min. Stereoisomers are assigned Isomers 1 and 2 in order of elution under the conditions described. Chiral purity was assessed under the following conditions; Column type: Chiralpak AD-H, 4.6 x 250mm, 5µm. Mobile phase = Methanol. Flow rate = 0.5 mL / min. UV detection: Waters 2998 PDA. ISOMER 1 (Example X55) 12.3 mg, 16%, pink-white solid1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.4 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.10 (dd, J = 8.7, 2.5 Hz, 1H), 7.24 (dd, J = 6.7, 2.3 Hz, 1H), 6.90 (dd, J = 6.7, 2.5 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.45 – 5.33 (m, 2H), 3.80 (dd, J = 13.7, 8.0 Hz, 1H), 3.20 (dd, J = 13.8, 5.3 Hz, 1H), 2.02 – 1.90 (m, 2H), 1.77 – 1.54 (m, 6H). LCMS (Method B), rt 2.74 min, [M+H]+m / z 323.1, purity 100%. Enantiomeric excess: 100% ISOMER 2 (Example X62) 12.3 mg, 16%, pink-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.3 Hz, 1H), 8.70 – 8.62 (m, 1H), 8.10 (dd, J = 8.7, 2.5 Hz, 1H), 7.24 (dd, J = 6.6, 2.3 Hz, 1H), 6.90 (dd, J = 6.6, 2.6 Hz, 1H), 6.84 (dd, J = 8.7, 0.7 Hz, 1H), 5.46 – 5.30 (m, 2H), 3.80 (dd, J = 13.8, 8.1 Hz, 1H), 3.20 (dd, J = 13.7, 5.3 Hz, 1H), 2.02 – 1.88 (m, 2H), 1.77 – 1.51 (m, 6H). LCMS (Method B), rt 2.73 min, [M+H]+m / z 323.1, purity 99%. Enantiomeric excess: 100%Scheme 2 - Synthesis of example X7Intermediate I1 methyl 2-methoxy-6-phenylpyridine-3-carboxylatemethyl 6-chloro-2-methoxypyridine-3-carboxylate (200 mg, 0.990 mmol), K2CO3 (420 mg, 3.04 mmol), phenylboronic acid (145 mg, 1.19 mmol) and Pd(PPh3)4 (115 mg, 0.100 mmol) were combined in dioxane (4 mL) and water (0.4 mL). The mixture was degassed by nitrogen sparge then stirred at 85 °C in a sealed reaction vessel for 2 h. After cooling the mixture was diluted with EtOAc (10 mL) and filtered over Celite®. The filter cake was washed twice with EtOAc (5 mL) and the filtrate washed with brine (20 mL). The combined organics were dried (MgSO4) and concentrated in vacuo, then purified by column chromatography (0-100% TBME in heptane) to give methyl 2-methoxy-6-phenylpyridine-3-carboxylate (242 mg, 92%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 7.9 Hz, 1H), 8.15 – 8.06 (m, 2H), 7.53 – 7.39 (m, 4H), 4.17 (s, 3H), 3.92 (s, 3H). LCMS Method A (ESI+), rt (min): 1.03, [M+H]+m / z 244.1, Purity: 94% Intermediate I2 Sodium 2-methoxy-6-phenylpyridine-3-carboxylatemethyl 2-methoxy-6-phenylpyridine-3-carboxylate (Intermediate I1, 242 mg, 0.995 mmol) was dissolved in methanol (3 mL), then 1 M NaOH(aq)(1.1 mL, 1.1 mmol) added. The reaction was stirred at RT overnight. The mixture was concentrated in vacuo and the resultant solid was triturated with Et2O (3 x 2 mL). After drying under vacuum, sodium 2-methoxy-6- phenylpyridine-3-carboxylate (217 mg, 87%) was obtained as a white solid.1H NMR (500 MHz, CD3OD) δ 8.10 – 8.06 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.46 – 7.42 (m, 3H), 7.40 – 7.36 (m, 1H), 4.06 (s, 3H). LCMS: Method C (ESI+), rt (min): 0.39, [M+H]+m / z: 230.1, Purity: 100% Example X7 - N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methoxy-6-phenylpyridine- 3-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (104 mg, 0.613 mmol) and sodium;2-methoxy-6-phenyl-pyridine-3-carboxylate (Intermediate I2, 140 mg, 0.558 mmol) were combined in DCM (3 mL), then DIPEA (0.30 mL, 1.7 mmol) was added, followed by T3P (0.43 mL, 0.72 mmol). The mixture was stirred at RT overnight. The mixture was quenched with NaHCO3(aq) and extracted with DCM, then dried through a hydrophobic phase separator and concentrated in vacuo. The residue was purified via preparative HPLC (Method 2, 215 nm). After lyophilization, N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methoxy-6- phenylpyridine-3-carboxamide (110 mg, 56%) was isolated as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.18 – 8.14 (m, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.56 – 7.46 (m, 3H), 7.24 (dd, J = 6.7, 2.3 Hz, 1H), 6.95 (dd, J = 6.7, 2.6 Hz, 1H), 5.43 – 5.36 (m, 1H), 4.09 (s, 3H), 3.78 (dd, J = 13.5, 7.8 Hz, 1H), 3.35 (dd, J = 13.5, 5.5 Hz, 1H). LCMS: Method D (ESI+), rt (min): 3.18, [M+H]+m / z: 345.1, Purity: 100%Scheme 3 - Synthesis of example X14 HC PhIntermediate I3 methyl 6-(2-phenylethynyl)pyridine-3-carbonitrileethynylbenzene (80 mg, 0.787 mmol), 6-bromopyridine-3-carbonitrile (120 mg, 0.656 mmol), CuI (1.2 mg, 6.6 µmol), PdCl2(PPh3)2 (4.6 mg, 6.6 µmol), triethylamine (1.4 mL, 9.8 mmol) and triphenylphosphane (1.7 mg, 6.6 µmol) were combined in anhydrous DMF (0.78 mL) and stirred at 60 °C for 18 h. After cooling the mixture was suspended in EtOAc (25 mL) then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (0- 30% EtOAc in heptane) to afford 6-(2-phenylethynyl)pyridine-3-carbonitrile (130 mg, 95%) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 9.12 – 8.99 (m, 1H), 8.49 – 8.29 (m, 1H), 7.94 – 7.81 (m, 1H), 7.69 – 7.62 (m, 2H), 7.54 – 7.46 (m, 3H). LCMS: Method A (ESI+), rt (min): 0.95, [M+H]+m / z: 205.2, Purity: 98% Intermediate I46-(2-phenylethynyl)pyridine-3-carboxylic acid6-(2-phenylethynyl)pyridine-3-carbonitrile (Intermediate I3, 140 mg, 0.686 mmol) and 5 M NaOH(aq) (1.4 mL, 6.9 mmol) were combined in ethanol (1.4 mL) and stirred at 60 °C for 2 h. The mixture was acidifed to ~pH 2 using 2 M HCl(aq), then extracted with 1:3 IPA:CHCl3 (3 x 15 mL). The combined organics were dried using a hydrophobic phase separator andconcentrated in vacuo to afford 6-(2-phenylethynyl)pyridine-3-carboxylic acid (140 mg, 91%) as an orange solid. LCMS: Method A (ESI+), rt (min): 0.76, [M+H]+m / z: 224.1, Purity: 99% Example X14 - N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(2-phenylethynyl)pyridine- 3-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (Intermediate I4, 40 mg, 0.24 mmol) was added to a mixture of 6-(2-phenylethynyl)pyridine-3-carboxylic acid (58 mg, 0.26 mmol), DIPEA (123 µL, 0.707 mmol) and HATU (134 mg, 0.354 mmol) in anhydrous DMF (0.8 mL). The mixture was stirred at RT for 0.5 h. The mixture was purified directly via preparative HPLC (Method 4, 215 nm) and lyophilised to afford N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)-6-(2-phenylethynyl)pyridine-3-carboxamide (49 mg, 60%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 6.5 Hz, 1H), 9.13 – 8.96 (m, 1H), 8.40 – 8.20 (m, 1H), 7.87 – 7.73 (m, 1H), 7.73 – 7.57 (m, 2H), 7.57 – 7.40 (m, 3H), 7.34 – 7.21 (m, 1H), 7.01 – 6.87 (m, 1H), 5.52 – 5.29 (m, 1H), 3.89 – 3.76 (m, 1H), 3.30 – 3.19 (m, 1H). LCMS: Method B (ESI+), rt (min): 2.58, [M+H]+m / z: 339.1, Purity: 98% Scheme 4 - Synthesis of example X20Intermediate I7 - ethyl 6-(cyclopentylamino)pyridine-3-carboxylateA mixture of ethyl 6-chloropyridine-3-carboxylate (100 mg, 0.539 mmol), cyclopentanamine (106 µL, 1.07 mmol) and K2CO3 (149 mg, 1.08 mmol) in anhydrous DMF (0.65 mL) was stirred at 100°C for 12 hours under N2(g). After cooling the mixture was partitioned into EtOAc and water then the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (0-20% TBME in heptane) to afford methyl 6-(cyclopentylamino)pyridine-3-carboxylate (92 mg, 66%) as a dark yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.3 Hz, 1H), 7.80 – 7.73 (m, 1H), 7.41 – 7.34 (m, 1H), 6.45 (d, J = 0.8 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.95 – 1.84 (m, 2H), 1.69 – 1.61 (m, 2H), 1.58 – 1.49 (m, 2H), 1.48 – 1.37 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 0.88 – 0.78 (m, 1H). LCMS: Method A (ESI+), rt (min): 0.63, [M+H]+, m / z: 235.2, Purity: 100% Intermediate I8 - methyl 6-(cyclopentylamino)pyridine-3-carboxylatemethyl 6-(cyclopentylamino)pyridine-3-carboxylate (Intermediate I7, 92 mg, 0.393 mmol) was suspended in THF (1 mL) and ethanol (1 mL) in a 7 mL pressure vial fitted with a magnetic stirrer bar.5 M NaOH(aq)(0.80 mL, 4.0 mmol) was added and the mixture was stirred at RT for 2 h. Further 5 M NaOH(aq)(0.80 mL, 4.0 mmol) was added and the mixture was stirred at RT for 72 h, then mixture was diluted with water (10 mL). The suspension was acidified to pH 1 using 1 M HCl(aq)then extracted using CHCl3 / IPA 50:50 (3 x 20 mL) and dried over Na2SO4, then concentrated in vacuo to afford 6-(cyclopentylamino)pyridine-3-carboxylic acid (67 mg, 83%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.40 – 8.29 (m, 1H), 8.11 – 7.99 (m, 1H), 7.03 – 6.93 (m, 1H), 4.30 – 4.20 (s, 1H), 3.80 – 3.74 (m, 1H), 2.09 – 1.94 (m, 2H), 1.77 – 1.65 (m, 2H), 1.63 – 1.50 (m, 4H). LCMS: Method A (ESI+), rt (min): 0.46, [M+H]+m / z: 207.2, Purity: 100%Example X20 - 6-(cyclopentylamino)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)pyridine-3-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (45 mg, 0.27 mmol) was combined with 6-(cyclopentylamino)pyridine-3-carboxylic acid (Intermediate I8, 67 mg, 0.33 mmol) in anhydrous DMF (0.3 mL), then HATU (144 mg, 0.379 mmol) and DIPEA (158 µL, 0.907 mmol) added. Stirred at RT for 2 h, then diluted with 1.8 mL 1:1 DMSO / MeOH and purified by preparative HPLC (Method 4, 288 nm) and dried under vacuum to afford 6- (cyclopentylamino)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide (18 mg, 20%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.72 – 8.65 (m, 1H), 8.54 – 8.48 (m, 1H), 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 7.22 (dd, J = 6.7, 2.3 Hz, 1H), 7.17 – 7.12 (m, 1H), 6.89 (dd, J = 6.7, 2.5 Hz, 1H), 6.48 – 6.41 (m, 1H), 5.39 – 5.30 (m, 1H), 4.21 – 4.08 (m, 1H), 3.83 – 3.73 (m, 1H), 3.22 – 3.14 (m, 1H), 1.98 – 1.87 (m, 2H), 1.73 – 1.62 (m, 2H), 1.60 – 1.50 (m, 2H), 1.49 – 1.38 (m, 2H). LCMS: Method D (ESI+), rt (min): 2.26, [M+H]+m / z: 322.2, Purity: 97% Scheme 5 - Synthesis of example X23Intermediate I10 - 4-(cyclopentyloxy)-3-fluorobenzoic acidmethyl 3-fluoro-4-hydroxybenzoate (160 mg, 0.940 mmol) and cyclopentanol (0.14 mL, 1.5 mmol) were dissolved in anhydrous toluene (3 mL), under N2(g), then CMBP (0.35 mL, 1.3 mmol) was added and the mixture heated to 90 C for 2 h under N2(g). After cooling the mixture was concentrated in vacuo and partially purified by column chromatography (0-25% EtOAc in heptane) to give a mixture of methyl 4-(cyclopentyloxy)-3-fluorobenzoate and cyclopentyl 4- (cyclopentyloxy)-3-fluorobenzoate. The mixture was suspended in THF (2.2 mL) and methanol (2.2 mL), then 5 M NaOH(aq) (2.2 mL, 11 mmol) was added and the mixture was stirred at RT for 4 h. The mixture was partially concentrated in vacuo to remove the organic solvent then acidified to pH 1 using 1 M HCl(aq) and extracted using EtOAc (3 x 20 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to afford 4-(cyclopentoxy)-3- fluorobenzoic acid (210 mg, 98%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 7.76 – 7.71 (m, 1H), 7.67 – 7.62 (m, 1H), 7.25 (t, J = 8.5 Hz, 1H), 5.01 – 4.95 (m, 1H), 2.01 – 1.91 (m, 2H), 1.81 – 1.66 (m, 4H), 1.65 – 1.56 (m, 2H). LCMS: Method A (ESI+), rt (min): 0.95, [M+MeCN+H]+m / z: 266.2, Purity: 98% Example X23 - 4-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-3- fluorobenzamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (33 mg, 0.20 mmol) and 4- (cyclopentoxy)-3-fluoro-benzoic acid (Intermediate I10, 40 mg, 0.18 mmol) were combined in anhydrous DMF (0.5 mL), followed by HATU (74 mg, 0.195 mmol) and DIPEA (62 µL, 0.36 mmol). Stirred at rt for 2 h, then diluted with 1.8 mL 1:1 DMSO / MeOH and purified via preparative HPLC (Method 4, 205 nm). Further purification via column chromatography (0- 60% EtOAc in Heptane) was undertaken to afford 4-(cyclopentyloxy)-N-(1,1-dioxo-2,3- dihydro-1λ⁶-thiophen-3-yl)-3-fluorobenzamide (42 mg, 69%) as a white solid1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 7.4 Hz, 1H), 7.74 – 7.66 (m, 2H), 7.27 – 7.21 (m, 2H), 6.88 (dd, J = 6.7, 2.5 Hz, 1H), 5.38 – 5.30 (m, 1H), 4.99 – 4.93 (m, 1H), 3.83 – 3.74 (m, 1H), 3.22 – 3.15(m, 1H), 1.99 – 1.90 (m, 2H), 1.77 – 1.66 (m, 4H), 1.64 – 1.53 (m, 2H). Method A, (ESI+), rt (min): 3.1, [M+H]+m / z: 340.1, Purity: 100% Prepared in a fashion analogous to Example X23 was Example X64 and intermediates I19 and I20. Table 2 Analytical data for example X64 and intermediates I19 and I20Scheme 6 - Synthesis of examples via carbonitrile intermediatesA representative example (Example X24) is detailed below. Intermediate I11 - 6-(cyclopentyloxy)pyridazine-3-carbonitrileSodium hydride (60% in mineral oil, 128 mg, 3.19 mmol) was added to a solution of cyclopentanol (264 µL, 2.90 mmol) in anhydrous THF (7.25 mL) under N2(g)in a dried flask at 0 ºC. The mixture was then stirred for 15 min then 6-chloropyridazine-3-carbonitrile (486 mg, 3.48 mmol) in anhydrous THF (7.25 mL) was added. The mixture was allowed to warm to RT and stirred for 18 h. The mixture was concentrated in vacuo, then partitioned between sat. NH4Cl(aq)(20 mL) and EtOAc (15 mL), then the aqueous phase was re-extraced with EtOAc (2 x 15 mL). The combined organics were dried over Na2SO4and concentrated in vacuo, then purified by column chromatography (0-50% EtOAc in heptane) to afford 6- (cyclopentyloxy)pyridazine-3-carbonitrile (320 mg, 58%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 5.63 (tt, J = 6.1, 2.7 Hz, 1H), 2.07 – 1.98 (m, 2H), 1.83 – 1.69 (m, 4H), 1.68 – 1.58 (m, 2H). LCMS: Method A (ESI+), rt (min): 0.90, [M+H]+m / z: 190.3, Purity: 99% Intermediate I12 - 6-(cyclopentyloxy)pyridazine-3-carboxylic acidA mixture of 6-(cyclopentoxy)pyridazine-3-carbonitrile (Intermediate I11, 100 mg, 0.529 mmol), 5 M NaOH(aq) (1.1 mL, 5.3 mmol) and ethanol (1 mL) was stirred at RT for 3 h, thenconcentrated in vacuo and purified by acidic automated reverse phase column chromatography (10 – 100% MeCN in 0.1% formic acid(aq)) to afford 6- (cyclopentyloxy)pyridazine-3-carboxylic acid (86 mg, 0.401 mmol, 76%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.62 (m, 1H), 2.08 – 1.98 (m, 2H), 1.82 – 1.68 (m, 4H), 1.68 – 1.57 (m, 2H). LCMS: Method A (ESI+), rt (min): 0.69, [M+H]+, m / z: 209.2, Purity: 97% Example X24 - 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)pyridazine-3-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (60 mg, 0.35 mmol) was added to a mixture of 6-(cyclopentyloxy)pyridazine-3-carboxylic acid (Intermediate I12, 81 mg, 0.39 mmol), DIPEA (185 µL, 1.06 mmol) and HATU (202 mg, 0.531 mmol) in anhydrous DMF (0.9 mL). The mixture was stirred at RT for 30 min then purified directly using preparative HPLC (Method 4, 215 nm) and lyophilised to afford 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶- thiophen-3-yl)pyridazine-3-carboxamide (63 mg, 55%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.70 (d, J = 7.7 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1H), 7.26 – 7.18 (m, 1H), 7.02 – 6.88 (m, 1H), 5.67 – 5.55 (m, 1H), 5.44 – 5.28 (m, 1H), 3.83 – 3.73 (m, 1H), 3.49 – 3.39 (m, 1H), 2.09 – 1.99 (m, 2H), 1.84 – 1.69 (m, 4H), 1.68 – 1.49 (m, 2H). LCMS: Method B (ESI+), rt (min): 2.64, [M+H]+, m / z: 324.1, Purity: 99% Prepared in an analogous fashion to scheme 6 and example X24, were intermediates in Table 3 and examples in Table 4. In parenthesis, (1) denotes a chloride starting material and (2) denotes a fluoride starting material. Table 3, Intermediates prepared in prepared in accordance with scheme 6Table 4, Examples prepared in accordance with scheme 6Example X255-(cyclopentyloxy)-N-[(3S)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl]pyrazine-2-carboxamide (ISOMER 1) and Example X465-(cyclopentyloxy)-N-[(3R)- 1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyrazine-2-carboxamide (ISOMER 2)Example X27 (40 mg) was subjected to chiral preparative chromatography under the following conditions; Column type: Cellulose-4, 21.2 x 250mm, 5µm. Mobile phase: 35% methanol: 65%CO2. Flow rate = 60 mL / min. Stereoisomers are assigned Isomers 1 and 2 in order of elution under the conditions described. Chiral purity was assessed under the following conditions; Column type: Cellulose-4, 4.6 x 250mm, 5µm. Mobile phase = 40% methanol: 60%CO2. Flow rate = 4 mL / min. UV detection: Waters 2998 PDA. ISOMER 1 - (S) isomer (Example X25) 19.1 mg, 48%, white solid1H NMR (400 MHz, DMSO-d6) δ 9.33 – 9.26 (m, 1H), 8.82 – 8.71 (m, 1H), 8.36 – 8.21 (m, 1H), 7.31 – 7.15 (m, 1H), 6.94 – 6.87 (m, 1H), 5.51 – 5.42 (m, 1H), 5.40 – 5.31 (m, 1H), 3.79 – 3.71 (m, 1H), 3.41 – 3.36 (m, 1H), 2.03 – 1.93 (m, 2H), 1.81 – 1.70 (m, 4H), 1.68 – 1.56 (m, 2H). LCMS (Method B), rt 2.76 min, [M+H]+m / z 324.1, purity 99%. Enantiomeric excess: 100% ISOMER 2 – (R) isomer (Example X46) 17.8 mg, 45%, white solid.1H NMR (400 MHz, DMSO-d6) δ 9.32 – 9.27 (m, 1H), 8.82 – 8.72 (m, 1H), 8.34 – 8.20 (m, 1H), 7.26 – 7.15 (m, 1H), 6.98 – 6.84 (m, 1H), 5.50 – 5.43 (m, 1H), 5.40 – 5.32 (m, 1H), 3.78 – 3.72 (m, 1H), 3.41 – 3.37 (m, 1H), 2.04 – 1.95 (m, 2H), 1.81 – 1.70 (m, 4H), 1.68 – 1.59 (m, 2H). LCMS (Method B), rt 2.76 min, [M+H]+m / z 324.1, purity 100%. Enantiomeric excess: 98% Scheme 7 - Synthesis of examples via acid starting materialsIntermediate I255-cyclobutoxypyrazine-2-carboxylic acidCyclobutanol (74 µL, 0.95 mmol) and 5-chloropyrazine-2-carboxylic acid (100 mg, 0.631 mmol) were dissolved in anhydrous NMP (2.5 mL), then KOtBu (180 mg, 1.60 mmol) added, then the mixture heated for 45 min at 120 °C under microwave irradiation. After cooling the mixture the pH was adjusted to 11 with sat. K2CO3(aq), then the solution was washed with DCM. The aqueous phase was then acidified to pH 2 with 2 M HCl(aq)and extracted with 3:1 CHCl3 / IPA. Combined extracts were dried (Mg2SO4) and concentrated in vacuo to afford 5- cyclobutoxypyrazine-2-carboxylic acid (280 mg, 98%) as a yellow oil. LCMS: Method A (ESI+), rt (min): 0.69, [M+H]+m / z: 195.3, Purity: 100% Example X265-cyclobutoxy-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide3‐amino‐2,3‐dihydro‐1λ⁶‐thiophene‐1,1‐dione hydrochloride (130 mg, 0.766 mmol) was dissolved in anhydrous DMF (1.5 mL), then 5-(cyclobutoxy)pyrazine-2-carboxylic acid (43%, 280 mg, 0.620 mmol) and HATU (254 mg, 0.668 mmol) added, followed by DIPEA (0.30 mL, 1.7 mmol). Stirred at RT for 1 h then diluted with 0.3 mL 1:1 DMSO / MeOH and purified by preparative HPLC (Method 1, 242 nm) then lyophilised to give 5-cyclobutoxy-N-(1,1-dioxo- 2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide (16 mg, 8%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 7.9 Hz, 1H), 8.74 (d, J = 1.3 Hz, 1H), 8.31 (d, J = 1.3 Hz, 1H), 7.19 (dd, J = 6.7, 2.4 Hz, 1H), 6.89 (dd, J = 6.7, 2.4 Hz, 1H), 5.39 – 5.31 (m, 1H), 5.27 – 5.18 (m, 1H), 3.78 – 3.70 (m, 1H), 3.41 – 3.35 (m, 1H), 2.46 – 2.37 (m, 2H), 2.18 – 2.05 (m, 2H), 1.87 – 1.77 (m, 1H), 1.74 – 1.62 (m, 1H). LCMS: Method B (ESI+), rt (min): 2.53, [M+H]+m / z: 310.2, Purity: 100% Prepared in an analogous fashion to scheme 7 and example X26, were intermediates in Table 5 and examples in Table 6. Table 5, intermediates prepared in accordance with scheme 7. Intermediate I26 employed DMF as a solvent. The remaining intermediates employed NMP as per intermediate I25 above.Table 6, Examples prepared in accordance with scheme 7. In parenthesis, (1) denotes the use of HATU for amide coupling as previously described and (2) denotes the use of T3P as described for Example X28.Example X34 N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1,1,1-trifluoropropan-2- yl)oxy]pyrazine-2-carboxamide-ISOMER 1 and Example X29 N-(1,1-dioxo-2,3-dihydro- 1λ⁶-thiophen-3-yl)-5-[(1,1,1-trifluoropropan-2-yl)oxy]pyrazine-2-carboxamide-ISOMER 2 and example X51 N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1,1,1-trifluoropropan- 2-yl)oxy]pyrazine-2-carboxamide-ISOMER 3 and Example X70 N-(1,1-dioxo-2,3-dihydro- 1λ⁶-thiophen-3-yl)-5-[(1,1,1-trifluoropropan-2-yl)oxy]pyrazine-2-carboxamide-ISOMER 4ISOMER 1 - EXAMPLE X34ISOMER 2 - EXAMPLE X29ISOMER 3 - EXAMPLE X51ISOMER 4 - EXAMPLE X70Example X30 (205 mg) was subjected to chiral preparative chromatography under the following conditions; Column type: Chiralpak AD-H, 10 x 250mm, 5µm. Mobile phase = 70:30 CO2:EtOH. Flow rate = 15 mL / min. Stereoisomers are assigned Isomers 1, 2, 3 and 4 in order of elution under the conditions described. Absolute configuration is undetermined. Chiral purity was assessed using the following conditions; Column type: Chiralpak AD-H, 4.6 x 250mm, 5µm. Mobile phase = 70:30 CO2:EtOH. Flow rate = 4 mL / min. UV detection Waters 2998 PDA. ISOMER 1 (Example X34) 33 mg, 15%, white solid1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 7.9 Hz, 1H), 8.80 (d, J = 1.3 Hz, 1H), 8.50 (d, J = 1.3 Hz, 1H), 7.19 (dd, J = 6.7, 2.4 Hz, 1H), 6.89 (dd, J = 6.7, 2.4 Hz, 1H), 6.01 – 5.87 (m, 1H), 5.41 – 5.30 (m, 1H), 3.74 (dd, J = 13.4, 7.9 Hz, 1H), 3.37 (dd, J = 13.4, 6.0 Hz, 1H), 1.50 (d, J = 6.5 Hz, 3H). Chiral analysis, rt 1.95 min, [M+H]+m / z 352.2, purity 100%. ISOMER 2 (Example X29) 32 mg, 14%, white solid.1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 7.9 Hz, 1H), 8.81 (d, J = 1.3 Hz, 1H), 8.51 (d, J = 1.3 Hz, 1H), 7.20 (dd, J = 6.7, 2.4 Hz, 1H), 6.90 (dd, J = 6.7, 2.4 Hz, 1H), 6.02 – 5.88 (m, 1H), 5.42 – 5.31 (m, 1H), 3.75 (dd, J = 13.4, 7.9 Hz, 1H), 3.38 (dd, J = 13.4, 6.0 Hz, 1H), 1.51 (d, J = 6.5 Hz, 3H). Chiral analysis, rt 2.37 min, [M+H]+ m / z 352.2, purity 100%. ISOMER 3 (Example X51) 29 mg, 13%, white solid.1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 7.7 Hz, 1H), 8.85 – 8.78 (m, 1H), 8.54 – 8.48 (m, 1H), 7.25 – 7.16 (m, 1H), 6.94 – 6.86 (m, 1H), 6.01 – 5.90 (m, 1H), 5.41 – 5.30 (m, 1H), 3.75 (dd, J = 13.3, 7.8 Hz, 1H), 3.39 (dd, J = 13.4, 5.9 Hz, 1H), 1.54 – 1.49 (m, 3H). Chiral analysis, rt 3.55 min, [M+H]+m / z 352.2, purity 100%. ISOMER 4 (Example X70) 25 mg, 11%, white solid.1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 7.9 Hz, 1H), 8.81 (d, J = 1.3 Hz, 1H), 8.50 (d, J = 1.3 Hz, 1H), 7.20 (dd, J = 6.7, 2.4 Hz, 1H), 6.89 (dd, J = 6.7, 2.4 Hz, 1H), 6.01 – 5.88 (m, 1H), 5.42 – 5.29 (m, 1H), 3.74 (dd, J = 13.4, 7.8 Hz, 1H), 3.38 (dd, J = 13.4, 6.0 Hz, 1H), 1.50 (d, J = 6.5 Hz, 3H). Chiral analysis, rt 4.17 min, [M+H]+m / z 352.2, purity 100%.Scheme 8 - Synthesis of examples via tert-butyl ester starting materialsIn some cases, the tert-butyl ester intermediates were not isolated and instead the corresponding acid was obtained directly following aqueous work up under acidic conditions, for example in the synthesis of Example X28 below. Intermediate I305-[(1s,3s)-3-fluorocyclobutoxy]pyrazine-2-carboxylic acid(1s,3s)-3-fluorocyclobutan-1-ol (84 mg, 0.93 mmol) was dissolved in THF (1 mL) then a solution oftBuOK (105 mg, 0.940 mmol) in THF (1 mL) added at 0 ºC. tert-butyl 5- chloropyrazine-2-carboxylate (100 mg, 0.470 mmol) was then added as a solution in THF (1 mL) and the mixture stirred for 16 h at RT. The mixture was adjusted to pH 2 with 1 M HCl(aq)and extracted with CHCl3 / IPA solution (3 x 10 mL). Organics concentrated to afford 5-[(1s,3s)- 3-fluorocyclobutoxy]pyrazine-2-carboxylic acid (100 mg, 89%) as a white solid. LCMS: Method A (ESI+), rt (min): 0.62, [M+H]+m / z: 213.1, Purity: 88% Example X28 N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1s,3s)-3- fluorocyclobutoxy]pyrazine-2-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (77 mg, 0.45 mmol) was added to a mixture of 5-(3-fluorocyclobutoxy)pyrazine-2-carboxylic acid (Intermediate I30, 100 mg,0.471 mmol), DIPEA (0.24 mL, 1.4mmol) and T3P (0.4 mL, 0.68 mmol) in anhydrous DMF (1.5 mL). The mixture was stirred at RT for 0.5 h. The mixture was purified directly via preparative HPLC (Method 3, 245 nm) and lyophilised to afford N-(1,1-dioxo-2,3-dihydro-1λ⁶- thiophen-3-yl)-5-[(1s,3s)-3-fluorocyclobutoxy]pyrazine-2-carboxamide (38 mg, 26%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.33 – 9.28 (m, 1H), 8.76 – 8.73 (m, 1H), 8.38 – 8.34 (m, 1H), 7.22 – 7.16 (m, 1H), 6.91 – 6.86 (m, 1H), 5.39 – 5.30 (m, 1H), 5.04 – 4.79 (m, 2H), 3.79 – 3.67 (m, 1H), 3.41 – 3.34 (m, 1H), 3.07 – 2.96 (m, 2H), 2.39 – 2.25 (m, 2H). LCMS: Method B (ESI+), rt (min): 2.26, [M+H]+m / z: 328.1, Purity: 100% In other cases, the tert-butyl ester intermediates were isolated (crude or pure) prior to formal deprotection with HCl in dioxane to give the acids, for example in the synthesis of Example X32 below. Intermediate I445-[(1r,3r)-3-fluorocyclobutoxy]pyrazine-2-carboxylic acidTo a solution of (1r,3r)-3-fluorocyclobutan-1-ol (84 mg, 0.93 mmol) in THF (1 mL) was added a solution oftBuOK (105 mg, 0.940 mmol) in THF (1 mL) at 0 ºC. tert-butyl 5-chloropyrazine- 2-carboxylate (100 mg, 0.470 mmol) was then added as a solution in THF (1 mL) and the mixture stirred for 16 h at RT. The mixture contained both ester and acid so was adjusted to pH 2 with 1 M HCl(aq)and extracted with CHCl3 / IPA solution (3 x 10 mL). Organics concentrated to afford tert-butyl 5-[(1r,3r)-3-fluorocyclobutoxy]pyrazine-2-carboxylate (156 mg, 44%) as a mix with the corresponding acid as an orange solid. This mixture was dissolved in 1,4-Dioxane (0.9 mL) and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) added, then the mixture stirred at 40 °C overnight. After cooling the mixture was diluted with CHCl3 / IPA (10 mL) and partitioned using a hydrophobic phase separator, then the organics concentrated in vacuo. The residue was then triturated with Et2O to afford 5-[(1r,3r)-3- fluorocyclobutoxy]pyrazine-2-carboxylic acid (100 mg, 75%) as a white solid. LCMS: Method A (ESI+), rt (min): 0.61, [M+H]+m / z: 213.1, Purity: 93%Example X32 N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1r,3r)-3- fluorocyclobutoxy]pyrazine-2-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (68 mg, 0.40 mmol) was added to a mixture of 5-(3-fluorocyclobutoxy)pyrazine-2-carboxylic acid (Intermediate I44, 93%, 100 mg, 0.438 mmol), DIPEA (0.20 mL, 1.2 mmol) and T3P (0.35 mL, 0.59 mmol) in anhydrous DMF (1.4 mL). The mixture was stirred at RT for 30 min, then purified by preparative HPLC (Method 3, 215 nm) and lyophilised to afford N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5- [(1r,3r)-3-fluorocyclobutoxy]pyrazine-2-carboxamide (25 mg, 19%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.35 – 9.29 (m, 1H), 8.79 – 8.74 (m, 1H), 8.39 – 8.34 (m, 1H), 7.24 – 7.19 (m, 1H), 6.93 – 6.88 (m, 1H), 5.50 – 5.42 (m, 1H), 5.42 – 5.33 (m, 1H), 5.35 – 5.25 (m, 1H), 3.80 – 3.71 (m, 1H), 3.43 – 3.36 (m, 1H), 2.79 – 2.66 (m, 2H), 2.64 – 2.53 (m, 2H). LCMS: Method B (ESI+), rt (min): 2.24, [M+H]+m / z: 328.1, Purity: 100% Prepared in an analogous fashion to scheme 8 and examples X28 / X32, were intermediates in Table 7 and examples in Table 8. In parenthesis, (1) denotes a carboxylic acid obtained directly following aqueous work up (as per Example X28). Otherwise, the tert-butyl ester intermediates were formally deprotected using HCl in dioxane (as per Example X32, (2) in parenthesis) Table 7 Intermediates prepared in accordance with scheme 8.Table 8 Examples prepared in accordance with scheme 8. *methyl cyclobutane diastereomers were separated achirally under preparative HPLC.Scheme 9 - Synthesis of examples via methyl or ethyl ester starting materialsor T3P, DIPEA,DCM, RTExample X59 representative procedure Intermediate I546-(2-cyclopentylethoxy)pyridine-3-carboxylic acidSodium hydride (60% in mineral oil, 52 mg, 1.3 mmol) was added to a stirred solution of 2- cyclopentylethanol (266 µL, 2.14 mmol) in THF (0.4 mL) under N2(g) at 0 ºC in a dried flask. The mixture was then stirred for 15 min before ethyl 6-chloropyridine-3-carboxylate (200 mg, 1.08 mmol) in THF (0.4 mL) was added and the mixture allowed to warm to RT and stir for 3 h. Water (1 mL) was added and the mixture stirred for 1 h then partially concentrated in vacuo to remove THF. The aqueous solution was then acidified with 2 M HCl(aq) to a pH of 3 and extracted with DCM (10 mL), then washed with brine and dried over MgSO4 and concentrated in vacuo. before being partially purified via acidic automated reverse phase column chromatography (10 – 100% MeCN in 0.1% formic acid(aq)) to afford a mixture which was suspended in THF (1.1 mL) and ethanol (1 mL).5M NaOH(aq) (0.44 mL, 2.2 mmol) was added and the mixture stirred at RT overnight. Further 5 M sodium hydroxide (0.44 mL, 2.2 mmol) was added and the mixture was stirred at RT for 4 h. The mixture was diluted with water (10 mL), then the suspension was acidified to pH 1 using 1 M HCl(aq)and extracted using EtOAc (3 x 20 mL). The combined organics were dried over Na2SO4and concentrated in vacuo to afford 6-(2-cyclopentylethoxy)pyridine-3-carboxylic acid (140 mg, 99%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.72 – 8.68 (m, 1H), 8.15 – 8.06 (m, 1H), 6.90 – 6.83 (m, 1H), 4.41 – 4.29 (m, 2H), 1.94 – 1.86 (m, 1H), 1.80 – 1.70 (m, 3H), 1.62 – 1.53 (m, 2H), 1.50 – 1.41(m, 2H), 1.32 (t, J = 7.1 Hz, 1H), 1.16 – 1.07 (m, 2H). LCMS: Method A, (ESI+), rt (min): 1.07, [M+H]+m / z: 236.2, Purity: 73% Example X596-(2-cyclopentylethoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)pyridine-3-carboxamide3‐amino‐2,3‐dihydro‐1 λ⁶‐thiophene‐1,1‐dione hydrochloride (62 mg, 0.37 mmol) was combined with 6-(2-cyclopentylethoxy)pyridine-3-carboxylic acid (73%, 140 mg, 0.434 mmol), in anhydrous DMF (0.9 mL), then HATU (85 mg, 0.22 mmol) and DIPEA (93 µL, 0.53 mmol) added. Stirred at rt for 2 h, then diluted with 1.8 mL 1:1 DMSO / MeOH and purified via preparative HPLC (Method 4, 243 nm) then dried in vacuo at 40 °C to give 6-(2- cyclopentylethoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide (33 mg, 26%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.5 Hz, 1H), 8.67 – 8.63 (m, 1H), 8.11 (dd, J = 8.7, 2.5 Hz, 1H), 7.24 (dd, J = 6.6, 2.3 Hz, 1H), 6.92 – 6.85 (m, 2H), 5.39 – 5.31 (m, 1H), 4.31 (t, J = 6.8 Hz, 2H), 3.79 (dd, J = 13.7, 8.1 Hz, 1H), 3.20 (dd, J = 13.7, 5.2 Hz, 1H), 1.95 – 1.82 (m, 1H), 1.81 – 1.69 (m, 4H), 1.63 – 1.52 (m, 2H), 1.51 – 1.44 (m, 2H), 1.18 – 1.07 (m, 2H). Method A, (ESI+), rt (min): 3.49, [M+H]+m / z: 351.2, Purity: 100% Prepared in analogous fashion to scheme 9 and example X59 were intermediates shown in table 9 and examples shown in table 10. The specific nature of the starting material used and core substitution pattern may be interpreted from the intermediate shown. Table 9 Intermediates prepared in accordance with scheme 9Table 10 Examples prepared in accordance with scheme 9. Example X54 was prepared using T3P in a manner analogous to Example X7. Otherwise, HATU was used. In the case of example X67, the pre-cursor acid intermediate was not isolated.Scheme 10 Synthesis of examples X52 and X53X53 Intermediate I592‐{[(tert‐butoxy)carbonyl]amino}‐4‐methanesulfonylbutanoateTo a mixture of methyl 2‐{[(tert‐butoxy)carbonyl]amino}‐4‐methanesulfonylbutanoic acid (620 mg, 2.20 mmol) and K2CO3 (455 mg, 3.29 mmol) in anhydrous DMF (12 mL) iodomethane (0.28 mL, 4.5 mmol) was added at 0 °C. The mixture was allowed to warm to RT and stirred for 14 h, then concentrated in vacuo, diluted with EtOAc (10 mL) and washed with water (3 x 10 mL). The organic was then washed with sat. NaHCO3(aq) (3 x 10 mL) and LiCl(aq) (2 x 10 mL) and brine (10 mL), then dried over MgSO4 and concentrated to afford methyl 2‐{[(tert‐ butoxy)carbonyl]amino}‐4‐methanesulfonylbutanoate (560 mg, 77%) as a colourless film which crystallised overnight to a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.0 Hz, 1H), 4.16 – 4.08 (m, 1H), 3.64 (s, 3H), 3.25 – 3.13 (m, 1H), 3.13 – 3.04 (m, 1H), 2.96 (s, 3H), 2.16 – 2.04 (m, 1H), 2.01 – 1.91 (m, 1H), 1.42 – 1.30 (m, 9H).Intermediate I60 tert-butyl N-(1,1,3-trioxo-1λ⁶-thian-4-yl)carbamateTo a solution of methyl 2‐{[(tert‐butoxy)carbonyl]amino}‐4‐methanesulfonylbutanoate (1.18 g, 4.00 mmol) in anhydrous THF (48 mL) was added KHMDS in THF (1 M, 8.0 mL, 8.0 mmol) dropwise at -78 °C under N2(g), then the mixture stirred at this temperature for 0.5 h. The mixture was allowed to warm to approx. -30 °C then quenched with sat. NH4Cl(aq) (1 mL) then diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine and dried over MgSO4, then concentrated in vacuo to afford tert-butyl N-(1,1,3-trioxo-1λ⁶-thian-4-yl)carbamate (944 mg, 90%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 7.24 – 7.14 (m, 1H), 4.86 – 4.79 (m, 1H), 4.50 – 4.41 (m, 1H), 4.05 – 3.98 (m, 1H), 3.77 – 3.63 (m, 1H), 3.51 – 3.44 (m, 1H), 2.25 – 2.17 (m, 1H), 1.87 – 1.75 (m, 1H), 1.39 (s, 9H). Intermediate I61 tert-butyl N-(3-hydroxy-1,1-dioxo-1λ⁶-thian-4-yl)carbamateTo a stirred solution of tert-butyl N-(1,1,3-trioxo-1λ⁶-thian-4-yl)carbamate (944 mg, 3.59 mmol) in MeOH (30 mL), NaBH4 (410 mg, 10.8 mmol) was added at 0 °C then the mixture was stirred at 35 °C for 1 h and quenched with sat. NH4Cl(aq), then extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (15 mL), dried over Na2SO4 , and concentrated to afford tert-butyl N-(3-hydroxy-1,1-dioxo-1λ⁶-thian-4-yl)carbamate (870 mg, 85%) as a white solid which was used in the next step without further purification.1H NMR (500 MHz, DMSO- d6) δ 6.95 – 6.82 (m, 1H), 5.33 (d, J = 5.0 Hz, 1H), 4.02 – 3.93 (m, 1H), 3.93 – 3.83 (m, 1H), 3.39 – 3.32 (m, 1H), 3.10 – 3.01 (m, 2H), 2.99 – 2.91 (m, 1H), 2.07 – 1.99 (m, 1H), 1.90 – 1.75 (m, 1H), 1.39 (s, 9H).Intermediate I62 tert-butyl N-[(4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4- yl]carbamate (ISOMER 1) and Intermediate I63 tert-butyl N-[(4S)-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-thiopyran-4-yl]carbamate (ISOMER 2)Intermediate I62 Intermediate I63ISOMER 1 ISOMER 2To a stirred solution of tert-butyl N-(3-hydroxy-1,1-dioxo-thian-4-yl)carbamate (820 mg, 3.09 mmol) in anhydrous DCM (20 mL), was added methanesulfonyl chloride (316 uL, 4.08 mmol) at 0 °C and stirred for 0.5 h. The mixture was diluted with water and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in pyridine (15.0 mL, 185 mmol) and heated to reflux for 4 h, then cooled, concentrated in vacuo and the residue purified via column chromatography (0-50 % EtOAc in heptane). The enantiomers were chirally separated (70:30 heptane:IPA, Chiralpak AS-H, 18ml / min), with isomers assigned 1 and 2 in order of elution under the conditions described giving tert-butyl N-[(4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-yl]carbamate I62 (197 mg, 26%, ISOMER 1) and tert-butyl N-[(4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4- yl]carbamate I63 (194 mg, 25%, ISOMER 2) as white solids. Enantiomeric excess 100% for both, 70:30 heptane:IPA, Chiralpak AS-H, 1 ml / min).1H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 11.1 Hz, 1H), 6.28 (d, J = 11.1 Hz, 1H), 4.33 – 4.23 (m, 1H), 3.39 – 3.34 (m, 2H), 2.30 – 2.10 (m, 2H), 1.40 (s, 9H). LCMS: Method A, rt (min): 0.67, no ionisation, Purity: 100%. Intermediate I64 (4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-aminium chlorideTFA (0.91 mL, 11.9 mmol) was added to a solution of tert-butyl N-[(4R)-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-thiopyran-4-yl]carbamate (Intermediate I62, 197 mg, 0.80 mmol) in DCM (3.3 mL). The mixture was stirred for 18 h, then concentrated in vacuo.4 M HCl(g)in dioxane (2.9 mL,11.6 mmol) was added to the residue and the resulting mixture stirred at RT for 30 min. The mixture was concentrated in vacuo and triturated with diethylether to give (4R)-1,1-dioxo-3,4- dihydro-2H-1λ⁶-thiopyran-4-aminium chloride (140 mg, 96%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 3H), 6.94 – 6.86 (m, 1H), 6.52 – 6.43 (m, 1H), 4.19 – 4.07 (m, 1H), 3.55 – 3.42 (m, 2H), 2.49 – 2.44 (m, 1H), 2.40 – 2.27 (m, 1H) Intermediate I65 (4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-aminium chlorideTFA (0.9 mL, 11.8 mmol) was added to a solution of tert-butyl N-[(4S)-1,1-dioxo-3,4-dihydro- 2H-1λ⁶-thiopyran-4-yl]carbamate (Intermediate I63, 194 mg, 0.78 mmol) in DCM (3.2 mL). The mixture was stirred for 18 h, then concentrated in vacuo.4 M HCl(g)in dioxane (2.8 mL, 11.2 mmol) was added to the residue and the resulting mixture stirred at RT for 30 min. The mixture was concentrated in vacuo and triturated with diethylether to give (4S)-1,1-dioxo-3,4- dihydro-2H-1λ⁶-thiopyran-4-aminium chloride (143 mg, 99%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 3H), 6.94 – 6.83 (m, 1H), 6.52 – 6.39 (m, 1H), 4.17 – 4.06 (m, 1H), 3.57 – 3.39 (m, 2H), 2.48 – 2.42 (m, 1H), 2.38 – 2.24 (m, 1H). Example X525-cyclobutoxy- -1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-yl]pyrazine-2-carboxamide(4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-aminium chloride (Intermediate I64, 28 mg, 0.15 mmol) was added to a mixture of 5-(cyclobutoxy)pyrazine-2-carboxylic acid (Intermediate I25, 26 mg, 0.13 mmol), DIPEA (80 µL, 0.46 mmol) and T3P (0.12 mL, 0.20 mmol) in anhydrous DMF (0.5 mL) and the mixture stirred at RT overnight under N2(g). Diluted with DMSO (0.4 mL) and purified via preparative HPLC (Method 1, 222 nm) and dried under high vacuum to afford to 5-cyclobutoxy-N-[(4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4- yl]pyrazine-2-carboxamide (19 mg, 44%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.22 – 9.13 (m, 1H), 8.73 (d, J = 1.3 Hz, 1H), 8.31 (d, J = 1.3 Hz, 1H), 6.70 – 6.61 (m, 1H),6.40 – 6.30 (m, 1H), 5.30 – 5.18 (m, 1H), 4.89 – 4.79 (m, 1H), 3.49 – 3.42 (m, 2H), 2.47 – 2.41 (m, 3H), 2.35 – 2.25 (m, 1H), 2.19 – 2.06 (m, 2H), 1.90 – 1.77 (m, 1H), 1.76 – 1.60 (m, 1H). LCMS: Method B, (ESI+), rt (min): 2.61, [M+H]+m / z: 324.3, Purity: 100% Example X535-cyclobutoxy-N-[(4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4- yl]pyrazine-2-carboxamide(4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-aminium chloride (Intermediate I65, 28 mg, 0.15 mmol) was added to a mixture of 5-(cyclobutoxy)pyrazine-2-carboxylic acid (Intermediate I25, 26 mg, 0.13 mmol), DIPEA (80 µL, 0.46 mmol) and T3P (0.12 mL, 0.20 mmol) in anhydrous DMF (0.5 mL) and the mixture stirred at RT overnight under N2(g). Diluted with DMSO (0.4 mL) and purified via preparative HPLC (Method 1, 222 nm) and dried under high vacuum to afford 5-cyclobutoxy-N-[(4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4- yl]pyrazine-2-carboxamide (21 mg, 49%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.22 – 9.12 (m, 1H), 8.73 (d, J = 1.3 Hz, 1H), 8.31 (d, J = 1.3 Hz, 1H), 6.70 – 6.61 (m, 1H), 6.40 – 6.30 (m, 1H), 5.30 – 5.18 (m, 1H), 4.90 – 4.80 (m, 1H), 3.50 – 3.42 (m, 2H), 2.48 – 2.42 (m, 3H), 2.36 – 2.23 (m, 1H), 2.22 – 2.05 (m, 2H), 1.88 – 1.77 (m, 1H), 1.76 – 1.63 (m, 1H). LCMS: Method B, (ESI+), rt (min): 2.61, [M+H]+m / z: 324.3, Purity: 100% Scheme 11 Synthesis of example X10Example I736-(cyclopentyloxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-1-one:A mixture of cyclopentanol (496 uL, 5.48 mmol) andtBuOK (307 mg, 2.74 mmol) in anhydrous NMP (4 mL) was stirred at RT for 10 min, then 6-chloro-3,4-dihydro-2H-2,7-naphthyridin-1- one (100 mg, 0.548 mmol) was added and the mixture was stirred at 180 °C for 1 h under microwave irradiation. The mixture was quenched with NH4Cl(aq)(15 mL) and then extracted with EtOAc (2 x 25 mL). The combined organics were dried over MgSO4and concentrated in vacuo. The crude was purified by column chromatography (20-100% EtOAc in heptane) then concentrated in vacuo, redissolved in EtOAc (25 mL) and washed with water (2 x 15 mL) and brine (2 x 15 mL) then dried over MgSO4to give 6-(cyclopentyloxy)-1,2,3,4-tetrahydro-2,7- naphthyridin-1-one (70 mg, 50%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.87 (s, 1H), 6.67 (d, J = 1.0 Hz, 1H), 5.43 – 5.39 (m, 1H), 3.37 – 3.33 (m, 2H), 2.85 (t, J = 6.5 Hz, 2H), 1.96 – 1.89 (m, 2H), 1.72 – 1.66 (m, 4H), 1.62 – 1.57 (m, 2H). Method B, (ESI+), rt (min): 0.76, [M+H]+m / z: 233.4, Purity: 91% Example X103-[6-(cyclopentyloxy)-1-oxo-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]-2,3- dihydro-1λ⁶-thiophene-1,1-dione:Sodium hydride (60% in mineral oil, 14 mg, 0.36 mmol) was added to a solution of 6- (cyclopentyloxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-1-one (Intermediate I73, 70 mg, 0.30 mmol) in anhydrous DMF (0.9 mL) at 0 °C, followed by 3-bromo-2,3-dihydro-1λ⁶-thiophene- 1,1-dione (107 mg, 0.54 mmol). The mixture was stirred at 0 °C for 1 h then poured into saturated NH4Cl(aq) (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 concentrated in vacuo. The residue was purified by preparative HPLC (Method 2, 215 nm) and lyophilised to afford 3-[6- (cyclopentyloxy)-1-oxo-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]-2,3-dihydro-1λ⁶-thiophene- 1,1-dione (6.3 mg, 6%) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.40 – 7.33 (m, 1H), 6.96 – 6.89 (m, 1H), 6.68 (s, 1H), 6.08 – 5.99 (m, 1H), 5.47 – 5.39 (m, 1H), 3.77 – 3.67 (m, 1H), 3.47 – 3.37 (m, 2H), 3.31 – 3.27 (m, 1H), 3.06 – 2.88 (m, 2H), 2.00 – 1.90 (m, 2H), 1.74 – 1.65 (m, 4H), 1.64 – 1.53 (m, 2H). Method B, (ESI+), rt (min): 2.90, [M+H]+m / z: 349.2, Purity: 100%Scheme 12 Synthesis of example X9Example I746-(cyclopentyloxy)-1,2-dihydro-2,7-naphthyridin-1-one:A mixture of cyclopentanol (1.22 mL, 13.4 mmol) andtBuOK (753 mg, 6.71 mmol) in anhydrous NMP (10 mL) was stirred at RT for 10 min, then 6-chloro-1,2-dihydro-2,7- naphthyridin-1-one (250 mg, 1.34 mmol) was added and the mixture was stirred at 180 °C for 1 h under microwave irradiation. The mixture was quenched with NH4Cl(aq) (15 mL) and extracted with EtOAc (2 x 25 mL), then the combined organics dried over MgSO4 and concentrated in vacuo. The mixture was purified by column chromatography (20-100% EtOAc in heptane) to afford 6-(cyclopentyloxy)-1,2-dihydro-2,7-naphthyridin-1-one (160 mg, 42%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.98 (s, 1H), 7.27 (app. t, J = 6.2 Hz, 1H), 6.84 (s, 1H), 6.39 (d, J = 7.2 Hz, 1H), 5.48 – 5.39 (m, 1H), 2.02 – 1.91 (m, 2H), 1.78 – 1.67 (m, 4H), 1.63 – 1.59 (m, 2H). LCMS: Method A, (ESI+), rt (min): 0.78, [M+H]+m / z: 231.2, Purity: 82% Example X9 3-[6-(cyclopentyloxy)-1-oxo-1,2-dihydro-2,7-naphthyridin-2-yl]-2,3- dihydro-1λ⁶-thiophene-1,1-dione:Synthesised in two batches and combined for purification. Batch 1: sodium hydride (60% in mineral oil, 6.7 mg, 0.17 mmol) was added to a solution of 6-(cyclopentyloxy)-1,2-dihydro-2,7- naphthyridin-1-one (Intermediate I74, 80%, 40 mg, 0.14 mmol) in anhydrous DMF (0.64 mL) at 0 °C, followed by 3-bromo-2,3-dihydro-1λ⁶-thiophene-1,1-dione (49 mg, 0.25 mmol) and sodium iodide (2.1 mg, 0.014 mmol). The reaction mixture was stirred at 0 °C for 18 h then combined with batch 2.Batch 2: Sodium hydride (60% in mineral oil, 20 mg, 0.50 mmol) was added to 6- (cyclopentyloxy)-1,2-dihydro-2,7-naphthyridin-1-one (80%, 120 mg, 0.417 mmol) in anhydrous DMF (1.3 mL) at 0 °C, followed by 3-bromo-2,3-dihydro-1λ⁶-thiophene-1,1-dione (148 mg, 0.750 mmol) and sodium iodide (6 mg, 0.04 mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture was combined with Batch 1, then poured into NH4Cl(aq)(15 mL) and extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method 4, 250 nm) and lyophilised to afford 3-[6-(cyclopentyloxy)-1-oxo- 1,2-dihydro-2,7-naphthyridin-2-yl]-2,3-dihydro-1λ⁶-thiophene-1,1-dione (6.4 mg, 4.1%) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.53 – 7.39 (m, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.11 – 7.04 (m, 1H), 6.88 (s, 1H), 6.61 – 6.55 (m, 1H), 6.16 – 6.08 (m, 1H), 5.49 – 5.41 (m, 1H), 3.93 – 3.83 (m, 1H), 3.52 – 3.47 (m, 1H), 2.02 – 1.94 (m, 2H), 1.80 – 1.69 (m, 4H), 1.65 – 1.57 (m, 2H). Method B, (ESI+), rt (min): 2.90, [M+H]+m / z: 347.1, Purity: 92% Scheme 13 Synthesis of example X11Intermediate I755-(cyclopentyloxy)-2,3-dihydro-1H-isoindol-1-one:CMBP (0.26 mL, 1.0 mmol) was added to a mixture of cyclopentanol (64 mg, 0.74 mmol) and 5-hydroxy-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.67 mmol) in anhydrous toluene (2.3 mL). The mixture was stirred at 90 °C for 2 h then concentrated in vacuo and purified by column chromatography (0-100% EtOAc in heptane) to afford 5-(cyclopentyloxy)-2,3-dihydro-1H- isoindol-1-one (130 mg, 88%) as a pale yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.57 – 7.50 (m, 1H), 7.09 – 7.05 (m, 1H), 6.98 – 6.94 (m, 1H), 4.94 – 4.85 (m, 1H), 4.30 (s, 2H), 1.99 – 1.91 (m, 2H), 1.77 – 1.67 (m, 4H), 1.64 – 1.57 (m, 2H). LCMS: Method B, (ESI+), rt (min): 0.78, [M+H]+m / z: 218.3, Purity: 99%Example X11 3-[5-(cyclopentyloxy)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-2,3-dihydro- 1λ⁶-thiophene-1,1-dione:Sodium hydride (60% in mineral oil, 29 mg, 0.72 mmol) was added to a solution of 5- (cyclopentyloxy)-2,3-dihydro-1H-isoindol-1-one (Intermediate I75, 130 mg, 0.598 mmol) in anhydrous DMF (1.8 mL) at 0 °C, then 3,4-dibromo-1λ⁶-thiolane-1,1-dione (212 mg, 1.08 mmol) added. The mixture was stirred at 0 °C for 1 h, then poured into NH4Cl(aq) (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method 4, 215 nm) and lyophilised to afford 3-[5-(cyclopentyloxy)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]-2,3-dihydro-1λ⁶-thiophene-1,1-dione (0.8 mg, 0.4%) as a white powder.1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 1H), 7.00 – 6.93 (m, 1H), 6.93 – 6.87 (m, 2H), 6.71 – 6.61 (m, 1H), 6.03 – 5.94 (m, 1H), 4.86 – 4.76 (m, 1H), 4.40 (d, J = 16.6 Hz, 1H), 4.22 (d, J = 16.6 Hz, 1H), 3.73 – 3.63 (m, 1H), 3.20 – 3.12 (m, 1H), 1.95 – 1.77 (m, 7H), 0.97 – 0.93 (m, 1H). Method B, (ESI+), rt (min): 3.00, [M+H]+m / z: 334.2, Purity: 95% Biological Assay 1

[0217] A functional WRN DNA strand displacement assay was used to evaluate inhibitors of WRN helicase activity.^Experiments were performed using a truncated WRN protein containing the helicase activity (aa 500-946), ATP and a DNA duplex substrate (E1: 5’-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTAC3-3’; E2: 5’- GCACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-3’) in the assay buffer (25 mM Tris-HCl (pH 7.8), 0.01% BSA, 0.01% Tween 20, 2 mM MgCl2, 50 mM NaCl, 1 mM DTT). E1 and E2 are respectively tagged with a BHQ2 fluorescence quencher (3’ end) and a cy3 fluorochrome (5’ end) (custom synthesis ATDBio Ltd, UK). 5 µL of assay buffer containing WRN protein (0.8 nM, 2-fold working concentration) was transferred into assay ready plates, containing 0.1 µL of compounds dissolved in DMSO and left to incubate for 30 min at 23°C. Reaction was then triggered by addition of 5 µL of WRN buffer containing DNA substrate (10 nM, 2-fold working concentration) and ATP (4 mM, 2-fold working concentration) and plates were incubated at 23°C for 25 min. Reaction was stopped using 5 µL of STOP buffer (40 mM Tris-HCl (pH 8.8), 20 mM EDTA, 6 nM Proteinase K) and fluorescence wasmeasured after 20 min, using Tecan F200 infinite plate reader (excitation / emission – 535 / 590nM). The reported IC50values shown in Table A below are the geometric means of at least 2 independent replicates. Table A - WRN*** denotes an IC50 of less than 10^M ** denotes an IC50 of 10^M to 50^M * denotes an IC50 of greater than 50^M

Claims

CLAIMS 1. A compound, or pharmaceutically acceptable salt thereof, having the structural formula I shown below:wherein: integer a is 1 or 2; X1is selected from N or CR1; X2is selected from N or CR2; X3 is selected from N or CR3; X4 is selected from N or CR4; wherein: R1 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2; R2 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2; R3 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2; R4 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy or NH2; with the proviso that: (i) up to three of X1, X2, X3 and X4 can be N; and (ii) up to three of R1, R2, R3 and R4 can be a substituent other than hydrogen; RN is hydrogen or RN and R1 are linked to form a fused 5 or 6-membered heterocyclic ring; RA is selected from halo, cyano, or a group: -LA-XA-QAwherein:LAis absent or (1-4C)alkylene, (2-4C)alkenylene or (2-4C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-, - C(O)-O-, -O-C(O)-, -S(O)0-2-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, -NR100a-, -N(R100a)-C(O)-NR100a-, -SO2N(R100a)- or -N(R100a)SO2-, where each R100agroup present is independently selected from hydrogen or (1- 2C)alkyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, -[CH2]n-(3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-aryl group -[CH2]n-heteroaryl group, wherein integer n is 0, 1, 2, 3 or 4; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1- 3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH.

2. A compound according to claim 1, wherein up to two of X1, X2, X3and X4are N.

3. A compound according to claim 1 or claim 2, wherein: (i) up to two of R1, R2, R3 and R4 is a substituent other than hydrogen; or (ii) only one of R1, R2, R3 and R4 can be a substituent other than hydrogen.

4. A compound according to any one of the preceding claims, wherein: X1 is selected from N or CR1; X2 is selected from N or CR2; X3 is selected from N or CR3; X4 is selected from N or CR4; wherein: R1 is selected from hydrogen, halo, methyl, methoxy or NH2; R2 is selected from hydrogen, halo, methyl, methoxy or NH2;R3is selected from hydrogen, halo, methyl, methoxy or NH2; R4is selected from hydrogen, halo, methyl, methoxy or NH2.

5. A compound according to any one of the preceding claims, wherein: X1is selected from N or CR1; X2is selected from N or CR2; X3is selected from N or CR3; X4is selected from N or CR4; R1is selected from hydrogen, methyl, methoxy or NH2; R2is selected from hydrogen, methyl, methoxy or NH2; R3is selected from hydrogen, methyl, methoxy or NH2; R4is selected from hydrogen, methyl, methoxy or NH2.

6. A compound according to any one of the preceding claims, wherein: (i) X1is CH, X2is CH, X3is CH, and X4is CH; (ii) X1is N, X2is CH, X3is CH, and X4is CH; (iii) X1is CH, X2is CH, X3is C-CH3and X4is CH; (iv) X1 is C-OCH3, X2 is N, X3 is CH and X4 is CH; (v) X1 is CH, X2 is CH, X3 is N and X4 is CH; (vi) X1 is CH, X2 is N, X3 is CH and X4 is CH; (vii) X1 is CH, X2 is CF, X3 is CH and X4 is CH; (viii) X1 is N, X2 is N, X3 is CH and X4 is CH; or (ix) X1 is CH, X2 is N, X3 is CH and X4 is N.

7. A compound according to any one of the preceding claims, wherein RN is hydrogen or RN and R1 are linked to form a -CH2-CH2- or -CH=CH- group.

8. A compound according to any one of the preceding claims, wherein RA is selected from halo, cyano, or a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene, (2-3C)alkenylene or (2-3C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)0-2-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, -NR100a-, -N(R100a)-C(O)-NR100a-, -SO2N(R100a)- or -N(R100a)SO2-, where each R100agroup present is independently selected from hydrogen or (1-2C)alkyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, -[CH2]n- (3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-aryl group -[CH2]n- heteroaryl group, wherein integer n is 0, 1, 2, 3 or 4; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH.

9. A compound according to any one of the preceding claims, wherein RAis selected from halo, cyano, or a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene or (2-3C)alkynylene; XAis absent or is selected from the group consisting of -O-, -C(O)-N(R100a)-, -N(R100a)-C(O)-, or -NR100a-, where each R100agroup present is independently selected from hydrogen or methyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, -[CH2]n- (3-6C)cycloalkyl, -[CH2]n-heterocyclyl group, -[CH2]n-phenyl group -[CH2]n- heteroaryl group, wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl or (1- 2C)alkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3 and X4 are CH.

10. A compound according to any one of the preceding claims, wherein RAis a group: -LA-XA-QAwherein: LAis absent or (1-3C)alkylene or (2-3C)alkynylene; XAis absent or is selected from -O- or -NR100a-, where R100ais selected from hydrogen or methyl; and QAis selected from the group consisting of hydrogen, or a (1-6C)alkyl, (3- 6C)cycloalkyl, heterocyclyl group, phenyl group or heteroaryl group, wherein integer n is 0, 1, 2, or 3; and any alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl group is optionally further substituted with one or more substituents selected from: halo, hydroxy, cyano, amino, (1-2C)alkyl or (1- 2C)alkoxy; and with the proviso that QAis not phenyl when LAand XAare absent, and all of X1, X2, X3and X4are CH.

11. A compound according to any one of the preceding claims, wherein RAis selected from:,with the proviso RA is not phenyl when all of X1, X2, X3 and X4 are CH;wherein: integer a, X1, X2, X3, X4, R1, R2,R3, R4, RNand RAeach have any of the meanings defined in claim 1; or X1, X2, X3, X4, R1, R2,R3, and R4are as defined in any one of claims 2 to 5; RNis as defined in claim 6; and RAis as defined in any one of claims 7 to 10.

13. A compound selected from any one of the following: 4-cyclohexyl-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)benzamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methyl-[1,1'-biphenyl]-4-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methoxy-6-phenylpyridine-3-carboxamide;3-[6-(cyclopentyloxy)-1-oxo-1,2-dihydro-2,7-naphthyridin-2-yl]-2,3-dihydro-1λ⁶-thiophene-1,1- dione; 3-[6-(cyclopentyloxy)-1-oxo-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]-2,3-dihydro-1λ⁶- thiophene-1,1-dione; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(2-phenylethynyl)pyridine-3-carboxamide; 6-(cyclopentylamino)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; 4-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)benzamide; 4-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-3-fluorobenzamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridazine-3-carboxamide; 5-(cyclopentyloxy)-N-[(3S)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyrazine-2-carboxamide; 5-cyclobutoxy-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1s,3s)-3-fluorocyclobutoxy]pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1,1,1-trifluoropropan-2-yl)oxy]pyrazine-2- carboxamide; rac-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1R,2R)-2-methylcyclobutoxy]pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1r,3r)-3-fluorocyclobutoxy]pyrazine-2- carboxamide; 5-(3,3-difluorocyclobutoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(2-methylcyclopentyl)oxy]pyrazine-2- carboxamide; 5-[(3,3-difluorocyclopentyl)oxy]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-(propan-2-yloxy)pyrazine-2-carboxamide; 5-{bicyclo[2.2.1]heptan-2-yloxy}-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; 5-(cyclohexyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-[(2,2-difluorocyclopentyl)oxy]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; rac-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(1R,2S)-2-methylcyclobutoxy]pyrazine-2- carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide;N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(4,4,4-trifluorobutan-2-yl)oxy]pyrazine-2- carboxamide; 5-[(1,1-difluoropropan-2-yl)oxy]-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; 5-(2,2-difluoropropoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-(cyclopentyloxy)-N-[(3R)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide; 5-cyclopropoxy-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2-carboxamide; 5-({6,6-difluorobicyclo[3.1.0]hexan-3-yl}oxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3- yl)pyrazine-2-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[3-(trifluoromethyl)cyclobutoxy]pyrazine-2- carboxamide; N-[(3R**)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]-5-{[(2R*)-1,1,1-trifluoropropan-2- yl]oxy}pyrazine-2-carboxamide; 5-cyclobutoxy-N-[(4R)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-yl]pyrazine-2-carboxamide; 5-cyclobutoxy-N-[(4S)-1,1-dioxo-3,4-dihydro-2H-1λ⁶-thiopyran-4-yl]pyrazine-2-carboxamide; 3-amino-5-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyrazine-2- carboxamide; 6-(cyclopentyloxy)-N-[(3S)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyridine-3-carboxamide; 6-(3-cyclopentylpropoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; 6-(2-cyclopentylethoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; 6-(cyclopentylmethoxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-(trifluoromethoxy)pyridine-3-carboxamide; 6-(cyclopentyloxy)-N-[(3R)-1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl]pyridine-3-carboxamide; N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-6-ethoxypyridine-3-carboxamide; 5-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-2-carboxamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-methylpyridine-3- carboxamide; 5-chloro-6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)pyridine-3- carboxamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-2-methylpyridine-3- carboxamide; 6-(cyclopentyloxy)-N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-4-methylpyridine-3- carboxamide;N-(1,1-dioxo-2,3-dihydro-1λ⁶-thiophen-3-yl)-5-[(3-methylcyclopentyl)oxy]pyrazine-2- carboxamide; or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in: (i) therapy; (ii) the treatment of a disease characterized by overexpression of WRN; (iii) the treatment of cancer (iv) the treatment of a cancer having microsatellite instability (MSI); and / or (v) the treatment of lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer.

16. A method of: (i) treating a disease characterized by overexpression of WRN; (ii) treating cancer (iii) the treatment of a cancer having microsatellite instability (MSI); and / or (iv) treating lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer;the method comprising administered to patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14.

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