Compounds comprising a naphthyridine or pyrido-pyrimidine core and a (hetero)aromatic-amino substituent

Abstract

Disclosed are compounds of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof: wherein R1, R2a, R2b, R3, R4, and R5 are as defined herein. Compounds of the invention may be suitable for use in treating diseases / conditions which are associated with PTC mutations. Also disclosed are pharmaceutical compositions comprising the compounds; and the compounds for use in treating conditions or disorders which are associated with PTC mutations in a subject.

Description

Compounds Comprising a Naphthyridine or Pyrido-Pyrimidine Core and a (Hetero)Aromatic-Amino Substituent

[0001] This invention relates to compounds comprising a pyridine-containing polycyclic core having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.BACKGROUND

[0002] When a ribosome encounters a termination sequence during the process of messenger RNA (mRNA) translation no cognate transfer RNA (tRNA) can bind. This leads to a halt in protein production, release factor (RF) proteins binding to the empty site on the ribosome and conformational changes in the ribosome that lead to the break-up of the ribosomal complex. Although accurate, translational termination is not 100% effective and its efficiency depends on competition between the recognition of the stop codon by eRF1 , and the decoding of the stop codon by a near-cognate tRNA (i.e. a natural suppressor tRNA). The latter case leads to the suppression of translation termination, also called “read-through”, where an amino acid is incorporated in place of the stop (Dabrowski, M. et al., RNA Biology 2015, 12, 950-958).

[0003] If the terminating codon occurs before the full length protein is made then the termination codon is a “premature” termination codon (PTC) and the truncated protein may not be functional. Normal terminating stop codons are usually in a genetic and structural context that reinforces their effectiveness and are usually more resistant to read-through than PTCs arising through truncating mutations (Wangen and Green, 2020 Elife 9:e52611).

[0004] Over 1800 separate inherited genetic disorders have been identified where the causative mutation in a proportion of individuals is a nonsense mutation where an in-frame, premature termination codon (PTC) leads to a loss of gene function (Kellermayer, R. European Journal of Medical Genetics 2006, 49, 445-450). Over 9,600 PTC mutations have been published, representing around 10% of all reported gene mutations (Krawczak, M. et al., Human Mutation 2000, 15, 45-51 , Mort, M. et al., Human Mutation 2008, 29, 1037-1047).

[0005] Nonsense mutations are involved in the pathology of a range of disorders; from polygenic pathologies such as cancer to monogenic diseases such as cystic fibrosis and Duchenne muscular dystrophy for which a PTC accounts for around 10% or 5-10% of all cases respectively (Keeling, K.M. & Bedwell, D.M., Journal of Molecular Medicine 2002, 80, 367-376, Kellermayer, R.European Journal of Medical Genetics 2006, 49, 445-450).

[0006] Whereas monogenetic diseases arise from either an inherited or de novo germline mutation, resulting in a PTC, in for example cancer, somatic mutations, can give rise to PTC mutations in tumour suppressor genes for example.

[0007] One of the surveillance systems used by the cell to remove abnormal mRNA transcripts that prematurely terminate translation is the non-sense mediated decay (NMD) pathway. It targets mRNA containing a PTC sequence more than ~50 base pairs upstream from the penultimate exon-exon junction (Maquat, L.E., Nature Reviews, Molecular Cell biology 2004, 5, 89-99).

[0008] The combination of premature termination of protein production and NMD of mRNA containing PTCs, can lead to almost total loss of protein production for mutant genes encoding a PTC.

[0009] Mechanisms by which translational read-though of PTC mutations may be achieved include but are not limited to: reducing the translational fidelity of the ribosome; reducing the efficiency of the translational termination machinery; inhibiting NMD; interfering with the regulation of gene transcription or translation or stabilising mRNA against NMD (Kellermayer, R European Journal of Medical Genetics 2006, 49, 445-450, Belgrader, P. J. C., and Maquat, L.E., Proc. Natl. Acad. Sci. USA 1993, 90, 482-486).

[0010] Agents which allow translational read-through of PTC mutations have the potential to treat any disease where the presence of a PTC in a gene is directly causative, a risk factor or an aggravating factor in disease.

[0011] Aminoglycosides (such as paromomycin, gentamicin, G418 / geneticin) are a class of antibiotics able to reduce translational fidelity. They exert their antibacterial action through inhibition of prokaryotic protein synthesis, however, at sub-lethal doses they lower translational fidelity of mammalian ribosomes leading to an increased rate of mis-incorporation of amino acids and also to an increased rate of translational read-through of stop codons (Davies, J. & Gorini, L., Proc. Natl. Acad. Sci. USA 1964, 51 , 883-8, Weinstein, Proc. Natl. Acad. Sci. USA 1964, 52, 988-996).

[0012] Aminoglycosides have been shown to allow read-through of PTC mutations in the CFTR gene responsible for cystic fibrosis in vitro (Bedwell, D.M., et al., Nature Medicine 1997, 3, 1280-1284) and in vivo, including patients (Ming Du, et al., Journal of Molecular Medicine 2002, 80, 595-604, Clancy, J.P. et al., Am J Respir Crit Care Med 2001 , 163, 1683-1692, Wilschanski, M., et al., The New England Journal of Medicine 2003, 139, 1433-1441).

[0013] In an animal model of Duchenne muscular dystrophy (DMD), 7 of 8 male mdx mice treated with 34 mg / kg gentamicin showed increased protection from contractile injury and 10-20% restoration of wild-type dystrophin levels (Barton-Davis, E.R., et al., Journal of Clinical Investigation 1999, 104, 375-381).

[0014] Gentamicin treatment induced functional type VII collagen in recessive dystrophic epidermolysis bullosa patients (Woodley, D. T. et al. Journal of Clinical Investigation 2017, 127, 3028-3038) with in vitro evidence supporting a read-through mechanism (Has, C. et al. Journal of Investigative Dermatology 2022, 142, 1227-1230).

[0015] The read-through of genes containing PTC mutations relevant to cystinosis, Hurler syndrome, inherited blindness and cancer genes have all been demonstrated following aminoglycoside treatment (Helip-Wooley, A., et al., Molecular Genetics and Metabolism 2002, 75, 128-133, Keeling, K.M., et al., Human Molecular Genetics 2001 , 10, 291-299, Moosajee, M.K., et al.,Human Molecular Genetics 2008, 17, 3987-4000). However, aminoglycosides are not suitable as PTC read-through agents due to the severe toxicity observed with high doses or repeated treatments.Triamterene pyrido[2,3-<y|pyrimidine-2,4-diamine

[0016] WO2019241633 describes compositions and methods for suppressing nonsense mutations, including the compound triamterene.

[0017] Hurlbert, B. S. et al. Journal of Medicinal Chemistry (1968), 11 (4), 711-17 describes 2,4-diaminopyrido[2,3-d]-pyrimidines, including pyrido[2,3-d]pyrimidine-2,4-diamine, with antibacterial and antiprotozoal effects.

[0018] WO2024194607 discloses pyrimido[4,5-b][1 ,5]naphthyridine-4,5(3h,10h)-dione derivatives for the treatment of diseases associated with PTC mutations, such as e.g. cancer.

[0019] Certain compounds of the present invention are suitable for use in treating diseases / conditions which are associated with PTC mutations.

[0020] A structurally novel class of compounds has now been found which provides PTC read-through agents.BRIEF SUMMARY OF THE DISCLOSURE

[0021] In accordance with a first aspect, the present invention provides a compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof:whereinX is N or CR6;R1is independently selected from Co-Ce-alkylene-R1a;R1ais independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, naphthyl, a 9- or 10-membered bicyclic heteroaromatic ring system, and a 5- to 7- membered cycloalkyl or heterocycloalkyl ring fused to a phenyl ring; wherein the monocyclic heteroaromatic ring or phenyl ring may be fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl, naphthyl, or heteroaromatic ring is selected from R10;R2ais independently at each occurrence selected from H and C1-C4 alkyl;R2bis independently at each occurrence selected from H, C1-C4 alkyl, Ci-C4-haloalkyl, C0-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-Ci-C4-alkyl, S(O)-Ci-C4-alkyl, and S(O)2-Ci-C4-alkyl;R2cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 8- membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis phenyl, or heteroaryl, R2cis optionally substituted with from 1 to 5 R10groups;R2dis independently selected from NR7R8and OR7; or R2aand R2b, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups;R3is independently selected from H, cyano, Ci-C4-alkylene-NR7R8, NR7R8, Ci-C4-alkylene- OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2- C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene-R3c, 0-Co-C4-alkylene-R3c, and Co-C4-alkylene-R3c;R3cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R3cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R3cis optionally substituted with from 1 to 4 R9groups; and where R3cis phenyl or heteroaryl, R3cis optionally substituted with from 1 to 5 R10groups;R4is independently selected from H, halo, cyano, Ci-C4-alkylene-NR7R8, NR7R8, C1-C4- alkylene-OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene-R4c, O-C0-C4- alkylene-R4c, and Co-C4-alkylene-R4c;R4cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis phenyl or heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups;R5is independently selected from H, halo, cyano, Ci-C4-alkylene-NR7R8, NR7R8, C1-C4- alkylene-OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene-R5c, O-C0-C4- alkylene-R5c, and Co-C4-alkylene-R5c;R5cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R5cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R5cis optionally substituted with from 1 to 4 R9groups; and where R5cis phenyl or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R3and R4together with the carbon atoms to which they are attached form a ring selected from: phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or e- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; or R4and R5together with the carbon atoms to which they are attached form a ring selected from: phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups;R6is independently selected from H, halo, Ci-Ce-alkyl, and Ci-Ce-haloalkyl;R7is independently at each occurrence selected from H and C1-C4 alkyl;R8is independently at each occurrence selected from H, C1-C4 alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl;R9is independently at each occurrence selected from =0, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, and Ci-C3-alkylene-NR7R8;R9ais independently at each occurrence selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R9ais cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups;R10is independently at each occurrence selected from halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, Ci-C3-alkylene-NR7R8, and Ci-Cs-alkylene-OR7; and wherein any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: Ci-C4-alkyl, Ci-C4-haloalkyl, oxo, halo, nitro, cyano, NRaRb, ORa, CRaRa-ORa, SRa, CO2Ra, C(O)Ra, CONRaRa, S(O)Ra, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and Ci-C4-alkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci-C4-alkyl.

[0022] Compounds according to formula (I) may be able to tautomerise, depending on the identity of the substituent groups, to give alternative tautomeric forms of the compound depicted above. It may be that compounds of formula (I) are a mixture of these tautomeric forms. Said tautomeric forms may be interconverting in any given sample. The relative proportion of tautomeric forms in a given sample will be determined by the position of an equilibrium between those tautomeric forms under the conditions. The position of the equilibrium, and therefore the extent to which each tautomeric form of the compound ispresent, may be determined by factors including, but not limited to, identity of the substituent groups, temperature, pH, and / or the solvent (where compound of formula (I) is in solution).

[0023] In an embodiment, the compound of formula (I) is a compound of formula (II):wherein R1, R2b, R3, R4and R5are as defined above for formula (I).

[0024] In an embodiment, the compound of formula (I) is a compound of formula (III):wherein R1, R3, R4and R5are as defined above for formula (I).

[0025] In an embodiment, the compound of formula (I) is a compound of formula (IV):wherein Ring A is independently selected from phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where Ring A is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring A is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; and wherein X, R1, R2b, R5, R9, and R10are as defined above for formula (I).

[0026] In an embodiment, the compound of formula (I) is a compound of formula (V):wherein Ring B is independently selected from phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where Ring B is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring B is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; and wherein X, R1, R2b, R3, R9, and R10are as defined above for formula (I).

[0027] In an embodiment, the compound of formula (I) is a compound of formula (VI):whereinR11and R12are independently selected from H, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci- C4-alkylene-ORaand Ci-C4-alkylene-NRaRb, or R11and R12, together with the carbon to which they are attached, form a 5- to 7-membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups;R13is either absent or, R12and R13, together with the atoms to which they are attached, form a 5- to 7-membered cycloalkyl or heterocycloalkyl ring optionally substituted with from 1 to 6 R9;Ring C is independently selected from a 5- or 6-membered monocyclic heteroaromatic ring and phenyl, optionally wherein Ring C is fused to phenyl, a 5- or 6- membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein Ring C or the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10;and wherein X, R2b, R3, R4, R5, R7, R8, R9, R9a, R10, Ra, and Rbare as defined above for formula (I).

[0028] In an embodiment, the compound of formula (I) is a compound of formula (VII):whereinR11and R12are independently selected from H, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci- C4-alkylene-ORaand Ci-C4-alkylene-NRaRb, or R11and R12, together with the carbon to which they are attached, form a 5- to 7-membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups;R13is either absent or, R12and R13, together with the atoms to which they are attached, form a 5- to 7-membered cycloalkyl or heterocycloalkyl ring optionally substituted with from 1 to 6 R9;Ring C is independently selected from a 5- or 6-membered monocyclic heteroaromatic ring and phenyl, optionally wherein Ring C is fused to phenyl, a 5- or 6- membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein Ring C or the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10;Ring A is independently selected from phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where Ring A is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring A is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; and wherein X, R2b, R5, R7, R8, R9, R9a, R10, Ra, and Rbare as defined above for formula (I).

[0029] In an embodiment, the compound of formula (I) is a compound of formula (VIII):whereinR11and R12are independently selected from H, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci- C4-alkylene-ORaand Ci-C4-alkylene-NRaRb, or R11and R12, together with the carbon to which they are attached, form a 5- to 7-membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups;R13is either absent or, R12and R13, together with the atoms to which they are attached, form a 5- to 7-membered cycloalkyl or heterocycloalkyl ring optionally substituted with from 1 to 6 R9;Ring C is independently selected from a 5- or 6-membered monocyclic heteroaromatic ring and phenyl, optionally wherein Ring C is fused to phenyl, a 5- or 6- membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein Ring C or the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10;Ring B is independently selected from phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where Ring A is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring A is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; and wherein X, R2b, R3, R7, R8, R9, R9a, R10, Ra, and Rbare as defined above for formula (I).

[0030] The following embodiments apply to compounds of any of formulae (l)-(VI 11) . These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) may be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass thatcompound may be combined to provide a further embodiment which forms part of the present disclosure.

[0031] R1may be independently selected from Ci-Ce-alkylene-R1a. R1may be Co-alkylene- R1a, i.e. , R1may be R1a. R1may be Ci-alkylene-R1a, e.g. -CH2-R1a. R1may be C2-alkylene-R1a. R1may be Cs-alkylene-R1a.

[0032] R1amay be independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, a 9- or 10-membered bicyclic heteroaromatic ring system, and a 5- to 7-membered cycloalkyl or heterocycloalkyl ring fused to a phenyl ring; wherein the monocyclic heteroaromatic ring or phenyl ring may be fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl, or heteroaromatic ring is selected from R10.

[0033] R1amay be independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, optionally wherein the monocyclic heteroaromatic ring is fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring; wherein R1ais optionally substituted with Co- Ce-alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a heteroaromatic ring is selected from R10.

[0034] R1amay be phenyl, optionally wherein the phenyl ring is fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring; wherein R1ais optionally substituted with Co-Ce-alkylene- R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl ring is selected from R10.

[0035] R1amay be independently selected from a 9- or 10-membered bicyclic heteroaromatic ring system; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents selected from R10.

[0036] R1amay be independently selected from a 5- to 7-membered cycloalkyl or heterocycloalkyl ring fused to a phenyl ring; wherein R1ais optionally substituted with Co-Ce- alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl ring is selected from R10.

[0037] R1amay be independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, naphthyl, a 9- or 10-membered bicyclic heteroaromatic ringsystem, and a 5- to 7-membered cycloalkyl ring fused to a phenyl ring; wherein the monocyclic heteroaromatic ring or phenyl ring may be fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl, or heteroaromatic ring is selected from R10.

[0038] R1amay be independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, a 9- or 10-membered bicyclic heteroaromatic ring system, and a 5- to 7-membered cycloalkyl ring fused to a phenyl ring; wherein the monocyclic heteroaromatic ring may be fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring and wherein the phenyl ring may be fused to a 5- to 7-membered cycloalkyl; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl, or heteroaromatic ring is selected from R10.

[0039] R1amay be independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, naphthyl, and a 9- or 10-membered bicyclic heteroaromatic ring system; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents selected from R10.

[0040] R1amay be independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, and a 9- or 10-membered bicyclic heteroaromatic ring system; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents selected from R10.

[0041] R1amay be a 5-membered monocyclic heteroaromatic ring; optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 3 substituents selected from R10. R1amay be imidazole; optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 3 substituents selected from R10. Thus, R1may be Co-Ce-alkylene-R1a, wherein R1ais imidazole; optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 3 substituents selected from R10. R1may be Ci-Cs-alkylene-R1a, wherein R1ais imidazole; optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 3 substituents selected from R10.

[0042] R1amay be a 5- to 7-membered heterocycloalkyl ring fused to a phenyl ring, wherein the heteroatom(s) in R1, including any substituents therein, is / are independently selected from the group consisting of O and S.

[0043] R1may be Co-Cs-alkylene-R1a, wherein R1ais a 5- to 7-membered heterocycloalkyl ring fused to a phenyl ring, wherein the heteroatom(s) in R1, including any substituents therein, is / are independently selected from the group consisting of O and S.

[0044] R2amay be independently selected from H and C1-C2 alkyl. R2amay be H.

[0045] R2bmay be independently selected from H, C1-C4 alkyl, Ci-C4-haloalkyl, C0-C4 alkyl- R2cand C2-C4-alkylene-R2d. R2bmay be independently selected from H, C1-C4 alkyl, and Co- 04 alkyl-R2c. R2bmay be independently selected from H, and C1-C4 alkyl. R2bmay be independently selected from H, and C1-C2 alkyl. R2bmay be H.

[0046] R2bmay be C2-C4-alkylene-R2d. R2dmay be NR7R8. R2dmay be OR7.

[0047] It may be that at least one of R2aand R2bis H. It may be that R2ais H and R2bis selected from H and methyl. It may be that R2aand R2bare each H.

[0048] It may be that R2bis independently at each occurrence selected from H, C1-C4 alkyl, Ci-C4-haloalkyl, C1-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-Ci-C4-alkyl, S(O)-Ci-C4-alkyl, and S(O)2-Ci-C4-alkyl.

[0049] It may be that R2bis C1.4 alkylene-R2c.

[0050] It may be that R2cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, 3- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6- membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis heteroaryl, R2cis optionally substituted with from 1 to 5 R10groups.

[0051] It may be that R2cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, 3- to 8-membered heterocycloalkyl, and 5- to 8-membered heterocycloalkenyl; wherein R2cis optionally substituted with from 1 to 4 R9groups.

[0052] X may be N. X may be CR6, e.g. CH.

[0053] R3may be H. R3may be Ci-C4-alkyl, e.g. methyl.

[0054] R4may be independently selected from H, halo, cyano, Ci-C4-alkylene-NR7R8, NR7aR8, Ci-C4-alkylene-OR7, OR7a, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene- R4c, 0-Co-C4-alkylene-R4c, and Co-C4-alkylene-R4c; wherein R7ais independently at each occurrence selected from C1-C4 alkyl.

[0055] R4may be independently selected from H, halo, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, 0-Co-C4-alkylene-R4c, and Co-C4-alkylene-R4c.

[0056] It may be that R4is independently selected from H, halo, cyano, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, 0-Co-C4-alkylene-R4c, and Co-C4-alkylene-R4c.

[0057] R4may be H. R4may be Ci-C4-alkyl, e.g. methyl.

[0058] R4cmay be independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups.

[0059] R3and R4together with the carbon atoms to which they are attached may form a ring selected from: Cs-Cy-cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 6 R9groups. R3and R4together with the carbon atoms to which they are attached may form a ring selected from: Cs-Cy-cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0060] R3and R4together with the carbon atoms to which they are attached may form a Cs- Cy-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R3and R4together with the carbon atoms to which they are attached may form a Cs-Cycycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0061] R3and R4together with the carbon atoms to which they are attached may form a Cs- cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R3and R4together with the carbon atoms to which they are attached may form a Cs-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0062] R5may be independently selected from H, halo, cyano, Ci-C4-alkylene-NR7R8, NR7aR8, Ci-C4-alkylene-OR7, OR7a, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene- R5c, 0-Co-C4-alkylene-R5c, and Co-C4-alkylene-R5c; wherein R7ais independently at each occurrence selected from Ci-C4alkyl.

[0063] It may be that R5is independently selected from H, halo, cyano, Ci-C4-alkylene- NR7R8, Ci-C4-alkylene-OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7,Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, 0-Co-C4-alkylene-R5c, and C0-C4- alkylene-R5c.

[0064] R5may be H. R5may be Ci-C4-alkyl, e.g. methyl.

[0065] R5may be R5c. R5cmay be phenyl optionally substituted with from 1 to 5 R10groups. R5cmay be 5-, or 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups. R5cmay be 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups.

[0066] R4and R5together with the carbon atoms to which they are attached may form a ring selected from: Cs-Cycycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 6 R9groups. R4and R5together with the carbon atoms to which they are attached may form a ring selected from: Cs-Cycycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0067] R4and R5together with the carbon atoms to which they are attached may form a C5- Cy-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R4and R5together with the carbon atoms to which they are attached may form a Cs-Cycycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0068] R4and R5together with the carbon atoms to which they are attached may form a C5- cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R4and R5together with the carbon atoms to which they are attached may form a Cs-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0069] Ring A may be independently selected from Cs-Cy-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring A is substituted with from 1 to 6 R9groups. Ring A may be independently selected from Cs-Cy-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring A is substituted with from 1 to 4 R9groups.

[0070] Ring A may be Cs-Cy-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring A may be Cs-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring A may be Cs-Cy-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring A may be Cs- cycloalkyl; optionally substituted with from 1 to 4 R9groups.

[0071] Ring B may be independently selected from Cs-Cy-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring B is substituted with from 1 to 6 R9groups. Ring B may be independently selected from Cs-Cy-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring B is substituted with from 1 to 4 R9groups.

[0072] Ring B may be Cs-Cy-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring B may be Cs-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring B may beCs-Cy-cycloalkyl; optionally substituted with from 1 to 4 R9groups. Ring B may be Cs- cycloalkyl; optionally substituted with from 1 to 4 R9groups.

[0073] R7may be H. R7may be C1-C4 alkyl.

[0074] R9may independently at each occurrence be selected from =0, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, and Ci-C3-alkylene-NR7R8.

[0075] R9may independently at each occurrence be selected from halo, NR7R8, OR7, CO2R7, CONR7R7, Ci-C4-alkyl, Ci-C3-alkylene-OR7, and Ci-C3-alkylene-NR7R8.

[0076] R9may independently at each occurrence be selected from F, Cl, Br, NR7R8, OR7, CO2R7, CONR7R7, Ci-C4-alkyl, Ci-C3-alkylene-OR7, and Ci-C3-alkylene-NR7R8.

[0077] R9may independently at each occurrence be selected from F, NR7R8, OR7, CO2R7, CONR7R7, Ci-C4-alkyl, Ci-C3-alkylene-OR7, and Ci-C3-alkylene-NR7R8.

[0078] R9may independently at each occurrence be selected from F, NR7R8, OR7, CO2R7, CONR7R7, and Ci-C4-alkyl.

[0079] R9amay independently at each occurrence be selected from C3-C8 cycloalkyl, phenyl, 3- to 8-membered heterocycloalkyl, and 5-, or 6-membered heteroaryl; wherein where R9ais cycloalkyl, or heterocycloalkyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups.

[0080] R9amay independently at each occurrence be C3-Cs cycloalkyl, optionally substituted with from 1 to 4 R9groups.

[0081] R9amay independently at each occurrence be phenyl, optionally substituted with from 1 to 5 R10groups.

[0082] R10may independently at each occurrence be selected from halo, cyano, OR7, C1- C4-alkyl, Ci-C4-haloalkyl, Ci-C3-alkylene-NR7R8, and Ci-C3-alkylene-OR7.

[0083] R10may independently at each occurrence be selected from halo, cyano, OR7, C1- C4-alkyl, and Ci-C4-haloalkyl.

[0084] R10may independently at each occurrence be selected from F, Cl, Br, cyano, OR7, Ci-C4-alkyl, and Ci-C4-haloalkyl.

[0085] R10may independently at each occurrence be selected from F, cyano, OR7, C1-C4- alkyl, and Ci-C4-haloalkyl.whereinR11and R12are independently selected from H, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci- C4-alkylene-ORaand Ci-C4-alkylene-NRaRb, or R11and R12, together with the carbon to which they are attached, form a 5- to 7-membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups;R13is either absent or, R12and R13, together with the atoms to which they are attached, form a 5- to 7-membered cycloalkyl or heterocycloalkyl ring optionally substituted with from 1 to 6 R9; andRing C is independently selected from a 5- or 6-membered monocyclic heteroaromatic ring and phenyl, optionally wherein Ring C is fused to phenyl, a 5- or 6- membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein Ring C or the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10.

[0087] R11and R12, together with the carbon to which they are attached, may form a 5- to 7- membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups. R11and R12, together with the carbon to which they are attached, may form a 5- membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups.

[0088] R11and R12may be independently selected from H, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, and Ci-C4-alkylene-ORa.

[0089] R11and R12may be independently selected from H, halo, Ci-C2-alkyl, Ci-C2-haloalkyl, and Ci-C4-alkylene-ORa.

[0090] R11may be H and R12may be independently selected from H, halo, Ci-C4-alkyl, Ci- C4-haloalkyl, and Ci-C4-alkylene-ORa.

[0091] R11may be H and R12may be independently selected from H, halo, Ci-C2-alkyl, Ci- C2-haloalkyl, and Ci-C4-alkylene-ORa.

[0092] R11and R12may be H.

[0093] R13may be absent. R12and R13, together with the atoms to which they are attached, may form a 5- to 7-membered cycloalkyl ring, optionally substituted with from 1 to 6 R9.

[0094] Ring C may be a 5- or 6-membered monocyclic heteroaromatic ring, optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 5 R10.

[0095] Ring C may be phenyl, optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 5 R10.

[0096] Ring C may be a 5- or 6-membered monocyclic heteroaromatic ring fused to phenyl, a 5- or 6-membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10.

[0097] Ring C may be phenyl fused to a 5- or 6-membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10.

[0098] In embodiments where R12and R13, together with the atoms to which they are attached, form a 5- to 7-membered heterocycloalkyl ring and Ring C is phenyl, the fragment, may not comprise a nitrogen atom.

[0099] In embodiments where R12and R13form a 5- to 7-membered heterocycloalkyl ring and Ring C is phenyl, any heteroatoms in the fragment, including any substituents therein, is / are independently selected from the group consisting of O and S.

[0100] In an embodiment, any of the alkyl, alkylene, alkenyl or cycloalkyl groups are optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: Ci-C4-alkyl, C1-C4- haloalkyl, CRaRa-ORa, oxo, fluoro, NRaRb, ORa, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and Ci-C4-alkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci-C4-alkyl.

[0102] In an embodiment, the compound is not a compound selected from List A:

[0103] In accordance with a second aspect, the present invention provides a pharmaceutical composition comprising a compound defined in the first aspect, and one or more pharmaceutically acceptable excipients. In embodiments of the second aspect, the compounds of List A are excluded. In embodiments of the second aspect, the compounds of List A are not excluded.

[0104] In accordance with a third aspect, the present invention provides a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect, for use as a medicament. In embodiments of the third aspect, the compounds of List A are excluded. In embodiments of the third aspect, the compounds of List A are not excluded.

[0105] In accordance with a fourth aspect, the present invention provides the use of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect, for the manufacture of a medicament. In embodiments of the fourth aspect, the compounds of List A are excluded. In embodiments of the fourth aspect, the compounds of List A are not excluded.

[0106] In accordance with a fifth aspect, the present invention provides a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect, for use in a method of treatment or prophylaxis of a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory orautoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome. In embodiments of the fifth aspect, the compounds of List A are excluded. In embodiments of the fifth aspect, the compounds of List A are not excluded.

[0107] In accordance with a sixth aspect, the present invention provides a method for the treatment or prophylaxis of a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome, said method comprising administering to a subject, an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect. In embodiments of the sixth aspect, the compounds of List A are excluded. In embodiments of the sixth aspect, the compounds of List A are not excluded.

[0108] In accordance with a seventh aspect, the present invention provides a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect, for use in a method of treatment or prophylaxis of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Alport syndrome, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome, and Retinitis Pigmentosa. In embodiments of the seventh aspect, the compounds of List A are excluded. In embodiments of the seventh aspect, the compounds of List A are not excluded.

[0109] In accordance with an eighth aspect, the present invention provides a method for the treatment or prophylaxis of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Alportsyndrome, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome, and Retinitis Pigmentosa. In embodiments of the eighth aspect, the compounds of List A are excluded. In embodiments of the eighth aspect, the compounds of List A are not excluded.

[0110] In accordance with a ninth aspect, the present invention provides the use of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect for the manufacture of a medicament for the treatment or prophylaxis of a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome. In embodiments of the ninth aspect, the compounds of List A are excluded. In embodiments of the ninth aspect, the compounds of List A are not excluded.

[0111] In accordance with a tenth aspect, the present invention provides a method of allowing translational read-through of PTC mutations in a subject, said method comprising administering to a subject an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect. In embodiments of the tenth aspect, the compounds of List A are not excluded.

[0112] In accordance with an eleventh aspect, the present invention provides a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect, for use in a method of treating conditions or disorders which are associated with a PTC mutation in a subject, said method comprising administering to a subject an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect. In embodiments of the eleventh aspect, the compounds of List A are excluded. In embodiments of the eleventh aspect, the compounds of List A are not excluded.

[0113] In accordance with a twelfth aspect, the present invention provides a method of treating conditions or disorders which are associated with a PTC mutation in a subject, saidmethod comprising administering to a subject an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect. In embodiments of the twelfth aspect, the compounds of List A are excluded. In embodiments of the twelfth aspect, the compounds of List A are not excluded

[0114] Suitably a PTC mutation may be any mutation which generates a premature termination codon (PTC) in a gene. Suitably a PTC mutation may be any mutation which generates an in-frame premature termination codon (PTC) in a gene. Suitably a PTC mutation occurs in the nucleotide sequence of a gene. Suitably a PTC mutation may occur in the coding region or non-coding region of a gene. Suitably a PTC mutation may occur in the coding region of a gene.

[0115] Suitably the mutation may be a point mutation, for example a substitution, deletion or insertion mutation. Suitably the mutation may be a substitution mutation. Suitably the substitution mutation may replace one nucleotide with another different nucleotide, suitably within the nucleotide sequence of a gene. Suitably the mutation may therefore be regarded as a nonsense mutation. Suitably the mutation may be a nonsense mutation which causes an in-frame PTC in a gene. Suitably the PTC may be any known termination codon such as TAG, TAA or TGA. Suitably the PTC may be TGA. Suitably therefore in some embodiments, the PTC mutation may be a substitution mutation which generates a PTC comprising TAG, TAA or TGA in a gene. Suitably therefore in some embodiments, the PTC mutation may be a substitution mutation of CGA to TGA or CAG to TAG in a gene.

[0116] A condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is directly or indirectly caused by a PTC mutation in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is directly caused by a PTC mutation in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is caused by a PTC mutation in one or more genes in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is directly caused by a PTC mutation in one or more genes in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is caused by a PTC mutation in one or more genes in a subject leading to a loss of function of the or each gene. Suitably reference herein to ‘a’ PTC mutation may be understood to refer to one or more PTC mutations, or a plurality of PTC mutations, suitably which may be present in one or more genes in a subject.

[0117] Suitably the one or more genes in which the PTC mutation is present are genes relating to one or more diseases as described herein. Suitably the one or more genes may bedirectly or indirectly linked with one or more diseases described herein. Suitably the one or more genes may contribute to, or cause, the phenotype of one or more diseases described herein. Such genes may be for example LAMB3, COL.7A, COL4, CFTR, and DMD, which are each associated with one or more of the diseases identified herein. In some embodiments, for example in which the disease is cancer, the one or more genes in which the PTC mutation is present may be cell cycle genes, tumour suppressor genes etc. Such tumour suppressor genes may include, for example, TP53, PTEN, APC, ARID1A or CTCF. Suitably such mutations may be regarded as driver mutations, suitably which drive a disease phenotype, such as tumour growth. Therefore, in some embodiments, the PTC mutation may be regarded as a driver mutation. In other embodiments, the one or more genes in which the PTC mutation is present may not contribute to or cause the disease phenotype. Suitably such mutations may be regarded as bystander mutations. Therefore in some embodiments, the PTC mutation may be regarded as a bystander mutation.

[0118] Conditions or disorders associated with a PTC mutation are well known in the art, and suitable such disorders which may be treated or prevented by the present invention are described hereinbelow. However, suitably, such disorders that are associated with PTC mutations may also be identified or determined by the use of standard molecular biology techniques. Suitably a condition or disorder may be determined as being associated with a PTC mutation by the use of molecular biology techniques, such as sequencing, single strand conformational polymorphism, denaturing gradient gel electrophoresis, heteroduplex analysis, or restriction fragment length polymorphism. Suitably a PTC mutation present in one or more genes of a subject which may cause a disease or condition can be identified using such techniques. Suitably, whole genome sequencing or whole exome sequencing may be used to identify a PTC mutation in one or more genes of a subject, suitably which may cause a disease or condition. Suitable methodologies may be described in Karagiannakos et al. Cancers (Basel) 2022, 14, 664, Stark et al. ‘A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders’ Genetics in Medicine, Volume 18, Issue 11 , 2016, North et al. ‘Approach to the diagnosis of congenital myopathies’ Neuromuscular Disorders, Volume 24, Issue 2, 2014, for example.

[0119] Suitably such techniques may be applied to a sample obtained from a subject suffering from a disease or condition or suspected of suffering from a disease or condition, suitably which may be caused by a PTC mutation. Suitably such techniques may comprise comparing a result from said sample, to a result obtained from a reference sample. Suitably a reference sample may be a sample of the same type from a healthy subject, suitably from an equivalent healthy subject of the same age, nationality, race, height, weight etc. Suitablesamples may include: a blood sample, serum sample, CNS fluid sample, tissue sample, cell sample, and the like. Suitably comparing a result in the context of the techniques above may comprise comparing the sequence of one or more genes from the subject suffering from a disease or condition to the sequence of the same one or more genes of the healthy subject. Suitably to identify PTC mutations within the one or more genes of the subject suffering from a disease or condition. Suitably such sequence comparisons may be carried out by available software, such as alignment software.

[0120] PTC read-through agents, such as the compounds disclosed herein, may in one or more embodiments, be of value and used in the treatment or amelioration of the following nonlimiting examples of disorders and diseases. Suitably any of the following disorders and diseases may be regarded as a disease or disorder associated with a PTC mutation in a subject. Suitably therefore the present invention provides a method of treating conditions or disorders which are associated with PTC mutations in a subject, wherein the conditions or disorders are selected from any listed in the following paragraphs.

[0121] The disease may be a disease of the musculoskeletal system. The disease of the musculoskeletal system may be a disease selected from Shwachman-Diamond Syndrome, Rickets, Laron Syndrome, Muscular Dystrophies (e.g. Duchenne muscular dystrophy (DMD)), Microcephaly, congenital limb deformities, Muscle Spasticity, Dwarfism, Gigantism, Osteopoikilosis, Cleidocranial Dysplasia, Synostosis, Mitochondrial Myopathies and Encephalomyopathies, Craniosynostoses, Mandibulofacial Dysostosis, Scoliosis, Osteoporosis, Osteopetrosis, Hyperostosis, Osteosclerosis, Osteogenesis Imperfecta, Holoprosencephaly, Acromegaly, Arthrogryposis, and Campomelic Dysplasia.

[0122] The disease may be a disease of the skin. The disease of the skin may be a disease selected from Ectodermal Dysplasia, Epidermolysis Bullosa, Focal Dermal Hypoplasia, Ichthyosis Vulgaris, Autosomal Recessive Congenital Ichthyosis (ARCI), Recessive X-linked Ichthyosis, Lamellar Ichthyosis, Congenital Ichthyosiform Erythroderma, Harlequin Ichthyosis, Epidermolytic Ichthyosis, Superficial Epidermolytic Ichthyosis, CHILD syndrome, Netherton syndrome, MEDNIK syndrome, Neutral lipid storage disease with ichthyosis, Atopic Dermatitis, Alopecia, Atrichia with papular lesions, Hypotrichosis, Incontinentia Pigmenti, Epidermolysis Bullosa Simplex, Lipodystrophy, Hidradenitis Suppurativa, Hyperpigmentation, Junctional Epidermolysis Bullosa, Oculocutaneous Albinism, Chronic Mucocutaneous Candidiasis, Chronic Mucocutaneous Ichthyosis, X-Linked Hypopigmentation, Cutis Laxa, Menkes Kinky Hair Syndrome, Palmoplantar Keratoderma, Ehlers-Danlos Syndrome, Congenital Monilethrix, Onychomycosis, Benign Familial Pemphigus, Albinism; Kindler syndrome, Cowden Syndrome, Xeroderma pigmentosum, epidermodysplasia verruciformis,Lipoid proteinosis, dyschromatosis symmetrica hereditaria, Striate keratodermas, Autosomal Recessive Congenital Anonychia, Focal dermal hypoplasia, and Skin fragility / woolly hair syndrome.

[0123] The disease may be a metabolic disease. The metabolic disease may be selected from Congenital Adrenal Hyperplasia, Inborn errors of Amino Acid Metabolism, Hypertriglyceridemia, Diabetes Mellitus, Type 1 and Type 2, Glycogen Storage Disease, Optic Atrophy, Calcinosis, Multiple Sulfatase Deficiency Disease, Fabry Disease, Hyperinsulinism, Familial Hypophosphatemia, Pseudohypoaldosteronism, Tangier Disease, Amyotrophic Lateral Sclerosis, Lactic Acidosis, Familial Amyloidosis, Mucopolysaccharidosis, Anemia, Sandhoff Disease, Cytochrome-c Oxidase Deficiency, Pyruvate Dehydrogenase Complex Deficiency Disease, Hypoglycemia, Neuronal Ceroid-Lipofuscinoses, Severe Combined Immunodeficiency, , Chronic Idiopathic Jaundice, Progeria, Hyponatremia, Wasting Syndrome, Cystinuria, Glycogen Storage Disease, Gaucher Disease, Hypolipoproteinemias, Oculocerebrorenal Syndrome, Smith-Lemli-Opitz Syndrome, Adrenoleukodystrophy, Ataxia Telangiectasia, Canavan Disease, Carbamoyl-Phosphate Synthase I Deficiency Disease, beta-Mannosidosis, and lysosomal storage diseases, wherein the lysosomal storage disease may be selected from Niemann-Pick Disease Mucopolysaccharidosis type 1 (Hurler syndrome), Mucopolysaccharidosis type 6, Mucopolysaccharidosis type 7, CLN1 disease, and CL3 disease.

[0124] The disease may be a disease of the Nervous System. The disease of the Nervous System may be selected from Rett Syndrome, Ataxias, Sensorineural Hearing Loss, Epilepsy, Charcot-Marie-Tooth Disease, Spinal Muscular Atrophy, Spastic Paraplegia, Hydrocephalus, Migraine with Aura, Chorea, Tremor, Usher Syndromes, De Lange Syndrome, Duane Retraction Syndrome, Dementia, Myoclonus, Hereditary Sensory and Autonomic Neuropathies, Intellectual Disability, X-linked Mental Retardation, Fragile X Syndrome, Hypopituitarism, Leukoencephalopathies, Dystonia, Congenital Pain Insensitivity, Tourette Syndrome, Alzheimers Disease, Parkinsons Disease, Angelman Syndrome, Apraxias, Cerebral Palsy, and Frontotemporal Dementia.

[0125] The disease may be a Cardiovascular disease. The cardiovascular disease may be selected from Coronary Disease, Ventricular Fibrillation, Telangiectasis, Kartagener Syndrome, Alagille Syndrome, Andersen Syndrome, Atrioventricular Block, and Cardiomyopathies.

[0126] The disorder may be an Endocrine disorder. The Endocrine disorder may be selected from Hypogonadism, Goiter, Fetal Macrosomia, Thyroid Hormone Resistance Syndrome,Gonadal Dysgenesis, Hypoparathyroidism, Neurogenic Diabetes Insipidus, and Androgen- Insensitivity Syndrome.

[0127] The disease may be a disease of the eye. The disease of the eye may be selected from Leber syndrome, Hereditary Optic Atrophies, Ectopia Lentis, Coloboma, Aphakia, and Choroideremia.

[0128] The disease may be a disease affecting the urogenital system. The disease affecting the urogenital system may be selected from Hypospadias, Hydrops Fetalis, Interstitial Nephritis, Polycystic Kidney Diseases, Alport Syndrome and Azoospermia.

[0129] The disease or disorder may be a haemic or lymphatic condition. The haemic or lymphatic condition may be selected from alpha- and beta-Thalassemia, Afibrinogenemia, Hemophagocytic Lymphohistiocytosis, Factor XI Deficiency, Hemophilia A, von Willebrand Diseases, Factor V Deficiency, Sideroblastic Anemia, Hereditary Elliptocytosis, Neutropenia, Chronic Granulomatous Disease, Hereditary Spherocytosis, Polycythemia, Hemophilia B, Factor VII Deficiency, Bernard-Soulier Syndrome, Dyserythropoietic Anemia, Hemolytic Anemia, Idiopathic Thrombocytopenic Purpura, Thrombasthenia, Factor XIII Deficiency, Hepatoerythropoietic Porphyria, and Acute Intermittent Porphyria.

[0130] The disease may be a respiratory disease. The respiratory disease may be selected from Cystic Fibrosis, Pulmonary Hypertension, Lipoid Proteinosis of Urbach and Wiethe, Newborn Respiratory Distress Syndrome, Chronic Obstructive Pulmonary Disease, Chronic Obstructive, Asthma, and Choanal Atresia.

[0131] The disease or disorder may be an inflammatory or autoimmune condition. The inflammatory or autoimmune condition may be selected from Immunologic Deficiency Syndromes, and Leukocyte-Adhesion Deficiency Syndrome.

[0132] The disease may be a disease of the Gastrointestinal system. Diseases of the gastrointestinal system may be selected from Chronic Hepatitis B, Colitis, Intestinal Polyposis, Inflammatory Bowel Diseases, Hirschsprung Disease, Exocrine Pancreatic Insufficiency, Crohn’s Disease, and Cholestasis.

[0133] The disease or disorder may be a Neoplasm. The Neoplasm may be selected from Acute Myeloid Leukemia, Paraganglioma, Rhabdoid Tumor, Rhabdomyoma, Adenoid Cystic Carcinoma, Large Cell Carcinoma, Lobular Carcinoma, Skin Appendage Carcinoma, Squamous Cell Carcinoma, Alveolar Rhabdomyosarcoma, Neuroectodermal Tumors, Multiple Hamartoma Syndrome, Pheochromocytoma, Nevus, Osteosarcoma, Teratoma, and Adenoma.

[0134] The disease or disorder may be cancer. The cancer may be selected from acoustic neuroma, anal cancer, bladder cancer, Bowen's disease, brain cancer, breast cancer, carcinomas including basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, choriocarcinoma, embryonal carcinoma, cystadenocarcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary carcinoma, papillary adenocarcinomas, renal cell carcinoma, sebaceous gland carcinoma, small cell lung carcinoma, squamous cell carcinoma, and sweat gland carcinoma, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, dysproliferative changes (dysplasias and metaplasias), endometrial cancer, ependymoma, esophageal cancer, essential thrombocythemia, estrogen-receptor positive breast cancer, Ewing’s tumour, genital cancer, cancer of the cervix, cancer of the vulva, vulvar intraepithelial neoplasia (VIN), cancer of the vagina, germ cell testicular cancer, gastrointestinal cancers, gastric cancer, glioblastoma, glioma, heavy chain disease, hemangioblastoma, hepatocellular cancer, hepatoma, hormone insensitive prostate cancer, keratinocyte carcinomas, kidney cancer, leukaemias including acute leukaemia, acute lymphocytic leukaemia, acute myeloid leukaemia, acute myelocytic leukaemia (monocyctic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukaemia, chronic leukaemia, chronic lymphocytic leukaemia, chronic myelocytic (granulocytic) leukaemia, chronic myelogenous leukaemia, erythroleukemia, lymphoblastic leukaemia, and myelogenous leukaemia, liver cancer, lung cancer, lymphoid malignancies of T-cell or B-cell origin, lymphomas (Hodgkin’s and non-Hodgkin’s) including cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, cutaneous (skin) lymphomas, malignancies and hyperproliferative disorders including of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, advanced malignancies, medulloblastoma, melanoma, meningioma, Merkel cell cancer mesothelioma, metastatic cancer, multiple myeloma, myeloma, pancreatic cancer, myelofibrosis, myeloproliferative neoplasms, neuroblastoma, non-small cell lung cancer, head and neck cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcomas including chondrosarcoma, endotheliosarcoma, fibrosarcoma, gliosarcoma, leiomyosarcoma, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, myxosarcoma, Castleman's disease and Kaposi's sarcoma, osteogenic sarcoma, and rhabdomyosarcoma, seminoma, skin cancer, skin adnexal tumors, and sarcomas, small cell lung cancer, solid tumors, stomach cancer, synovioma, testicular tumours, thyroid cancer, uterine cancer, Waldenstrom’s macroglobulinemia, and Wilms’ tumour.

[0135] The disease or disorder may be selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.

[0136] The disease or disorder may be selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Alport Syndrome, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, and ciliopathies (such as Usher syndrome or Retinitis Pigmentosa).

[0137] The disease or disorder may be selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Duchenne Muscular Dystrophy, Cystic Fibrosis, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma and Familial adenomatous polyposis. Suitably such disorders may be associated with a PTC mutation in a subject. Suitably for example, the disease may be Junctional epidermolysis bullosa, associated with a PTC mutation in the LAMB3 gene. Suitably for example, the disease may be Recessive dystrophic epidermolysis bullosa, associated with a PTC mutation in the COL.7A1 gene. Suitably for example, the disease may be Duchenne Muscular Dystrophy, associated with a PTC mutation in the DMD gene. Suitably for example, the disease may be Cystic Fibrosis associated with a PTC mutation in the CTFR gene. Suitably for example, the disease may be Familial adenomatous polyposis associated with a PTC mutation in the APC gene. Suitably for example, the disease may be a cancer as listed above associated with a PTC mutation in a gene selected from: TP53, PTEN, ARID1A or CTCF.

[0138] Suitably, therefore, the present invention provides a method of treating conditions or disorders which are associated with PTC mutations in a subject, wherein the condition or disorder associated with PTC mutations in a subject is selected from recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I,Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Ciliopathies (such as Usher syndrome or Retinitis Pigmentosa), and Alport Syndrome. In some embodiments, the present invention provides a method of treating conditions or disorders which are associated with PTC mutations in a subject, wherein the condition or disorder associated with PTC mutations in a subject is selected from recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Duchenne Muscular Dystrophy, Cystic Fibrosis, and Familial adenomatous polyposis.

[0139] PTC read-through agents, such as the compounds disclosed herein, may in one or more embodiments, also be of value and used in the palliation, diagnosis or prevention of any disease, disorder or condition in humans of one or more of the aforesaid non-limiting examples of disorders and diseases. Suitably any of the aforesaid disorders and diseases may be regarded as a disease or disorder associated with a PTC mutation in a subject. Suitably therefore the present invention further provides a method of palliation, diagnosis or prevention of conditions or disorders which are associated with PTC mutations in a subject, wherein the conditions or disorders are selected from any listed in the aforesaid paragraphs.

[0140] Treatment or amelioration with PTC read-through agents, such as compositions comprising the compounds disclosed herein or salts thereof (or combinations thereof), in some embodiments may be effective if administered orally. In some other embodiments may be effective if applied topically, and in some further embodiments may be effective if applied topically and orally.

[0141] In some embodiments, compositions comprising a novel compound disclosed herein or salt thereof (or combinations thereof) may be administered to young children. In some embodiments, compositions comprising a compound of the invention or salt thereof (or combinations thereof) may be administered to adolescents or teenagers. In some embodiments, compositions comprising a compound of the invention or salt thereof (or combinations thereof) may be administered to adults.DETAILED DESCRIPTION

[0142] The term Cm-Cnrefers to a group with m to n carbon atoms. For the absence of doubt, the term “Co” refers to a group with 0 carbon atoms.

[0143] The term “alkyl” refers to a monovalent linear or branched saturated hydrocarbon chain. For example, Ci-Ce-alkyl may refer to methyl, ethyl, n-propyl, / so-propyl, n-butyl, secbutyl, terf-butyl, n-pentyl and n-hexyl. The alkyl groups may be unsubstituted or substituted by one or more substituents.

[0144] The term “alkylene” refers to a bivalent linear saturated hydrocarbon chain. For example, Ci-Cs-alkylene may refer to methylene, ethylene or propylene. The alkylene groups may be unsubstituted or substituted by one or more substituents. For the absence of doubt, the term “Co-alkylene” refers to a group in which an alkylene chain is absent. For example, “Co-alkylene-Ra” refers to an Ra.

[0145] The term “haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-Ce-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2- trichloroethyl, fluoroethyl e.g. 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A haloalkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one fluorine atom. Thus, a haloalkyl group may have any amount of halogen substituents. The group may contain a single halogen substituent, it may have two or three halogen substituents, or it may be saturated with halogen substituents.

[0146] The term “alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkenyl” may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl groups may be unsubstituted or substituted by one or more substituents.

[0147] The term “alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond. The triple bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkynyl” may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl groups may be unsubstituted or substituted by one or more substituents.

[0148] The term “cycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, “Cs-Ce-cycloalkyl” may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl groups may be unsubstituted or substituted by one or more substituents.

[0149] The term “y- to z-membered heterocycloalkyl” refers to a y- to z- membered heterocycloalkyl group. Thus it may refer to a monocyclic or bicyclic saturated group having from y to z atoms in the ring system and comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring systemare selected from O, S and N). Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetra hydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine. A heterocycloalkyl group may be unsubstituted or substituted by one or more substituents. Heterocycloalkyl groups may be monocyclic. Heterocycloalkyl groups may be bicyclic. Bicyclic heterocycloalkyl groups may be fused, spirofused or bridged groups.

[0150] The term “heterocycloalkyl ring fused to a phenyl ring” may mean bicyclic ring systems in which one ring of the bicyclic ring system is a saturated heterocycloalkyl ring and the other ring is phenyl. For example, the term “heterocycloalkyl ring fused to a phenyl ring” may refer to the group:-membered heterocycloalkyl group fused to a phenyl ring. It may be that, when R1ais a “heterocycloalkyl ring fused to a phenyl ring”, R1does not comprise a nitrogen atom. Thus, where R1ais a heterocycloalkyl ring fused to a phenyl ring, it may be that the heteroatom(s) in R1is / are independently selected from the group consisting of O and S. For example, R1may

[0151] The term “cycloalkyl ring fused to a phenyl ring” may mean bicyclic ring systems in which one ring of the bicyclic ring system is phenyl and the other ring is a saturated cycloalkyl ring. For example, the term “cycloalkyl ring fused to a phenyl ring” may refer to the group:, e.g., a 5-membered cycloalkyl group fused to a phenyl ring.

[0152] The term “monocyclic heteroaromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring” may mean bicyclic ring systems in which one ring of the bicyclic ring system is a 5-, or 6-membered monocyclic heteroaromatic ring, and the other ring is a saturated 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring. For example, the term “monocyclic heteroaromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring” may refer to the group:, e.g., a monocyclic 6-membered heteroaromatic ring fused to a 6-membered cycloalkyl ring.

[0153] The term “phenyl ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring” may mean bicyclic ring systems in which one ring of the bicyclic ring system is phenyl and the other ring is a saturated 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring. For example, the term “phenyl ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkylY ring” may refer to the group: , e.g., a 5-membered cycloalkyl group fused to a phenyl ring.

[0154] Aryl groups may be any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1 )TT electrons). Aryl groups may have from 6 to 10 carbon atoms in the ring system. Aryl groups will typically be phenyl groups. Aryl groups may be naphthyl groups or biphenyl groups.

[0155] The term ‘heterocycloalkyl’ group or ring refers to rings comprising from 1 to 4 heteroatoms independently selected from O, S and N.

[0156] The term ‘heterocycloalkenyl’ refers to partially saturated rings comprising from 1 to 2 heteroatoms independently selected from O, S and N.

[0157] The term “heteroaryl” or “heteroaromatic” refers to any aromatic (i.e. a ring system containing 2(2n + 1 )TT electrons) ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, isoquinoline, indole, benzofuran, benzopyrazole, benzimidazole. The term “heteroaryl” also encompasses groups that are tautomers of hydroxy heteroaryl groups, such as pyridones, and tautomers of hydroxy heteroaryl groups that are substituted on the nitrogen, such as N-alkyl pyridones.

[0158] Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis / trans (or Z / E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of theinvention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0159] Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

[0160] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[0161] Conventional techniques for the preparation / isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[0162] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[0163] Throughout the specification, a down or up wedge bond (i.e.or jSused to depict absolute configuration. Where a down or up wedge bond is used at a particular position, the compound has substantially a single configuration (either R or S) at the indicated position. A down or up rectangular bond (i.e.or ^ ) is used to depict relative stereochemistry between two positions. Where a down or up rectangular bond is used at a chiral centre, the compound is in the form of a mixture (typically a 1 :1 mixture) of R and S configurations at the indicated position.

[0164] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneousform of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0165] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[0166] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0167] Compounds and salts described in this specification may be isotopically-labelled (or “radio-labelled”). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include2H (also written as “D” for deuterium),3H (also written as “T” for tritium),11C,13C,14C,150,170,180,13N,15N,18F,36CI,123l,25l,32P,35S and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays,3H or14C are often useful. For radio-imaging applications,11C or18F are often useful. In some embodiments, the radionuclide is3H. In some embodiments, the radionuclide is14C. In some embodiments, the radionuclide is11C. And in some embodiments, the radionuclide is18F.

[0168] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[0169] The selective replacement of hydrogen with deuterium in a compound may modulate the metabolism of the compound, the PK / PD properties of the compound and / or the toxicity of the compound. For example, deuteration may increase the half-life or reduce the clearance of the compound in vivo. Deuteration may also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It is to be understood that the invention encompasses deuterated derivatives of compounds of formula (I). As used herein, the term deuterated derivative refers to compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Accordingly, in a compound of the invention one or more hydrogen atom is optionally replaced by deuterium. For example, one or more hydrogen atoms in a Ci-4-alkyl group may be replaced by deuterium to form a deuterated Ci-4-alkyl group. By way of example, if any of R2a, R2b, R3, R4, R5, R6, R7, R7a, R8, R9, or R10is methyl, the invention also encompasses -CDs, -CHD2 and -CH2D. Similarly R2a, R2b, R3, R4, R5, R6, R7, or R8may be D.

[0170] The activity of the compounds of the present invention can be assessed by a variety of in silico, in vitro and in vivo assays. In silico analysis of a variety of compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.

[0171] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as 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, / .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, / .e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0172] A “therapeutically effective amount” includes the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect 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.

[0173] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0174] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0175] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 % w / w compounds of the invention, more preferably from 0.05 to 80 % w / w compounds of the invention, still more preferably from 0.10 to 70 % w / w compounds of the invention, and even more preferably from 0.10 to 50 % w / w compounds of the invention (all percentages by weight being based on total composition).

[0176] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, ointments, gels, lotions, solutions, suspensions; or systemically, e.g. by oral administration in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs; or by parenteral administration in the form of a sterile aqueous or oily solution, suspension or emulsion for injection (including intravenous, intracoronary, subcutaneous, intramyocardial, intraperitoneal, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories or enemas; by inhalation for example as a finely divided powder or a liquid aerosol; or for administration by insufflation (for example as a finely divided powder).

[0177] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and / or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0178] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balancebeing sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and / or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[0179] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[0180] The size of the dose for therapeutic or prophylactic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the concentration of the compound required for effectiveness in isolated cells, the concentration of the compound required for effectiveness in experimental animals, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0181] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.

[0182] An effective amount of a compound of the present invention for use in therapy of a condition is an amount sufficient to achieve symptomatic relief in a warm-blooded animal, particularly a human of the symptoms of the condition, to mitigate the physical manifestations of the condition, or to slow the progression of the condition.

[0183] 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 host 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 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 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.

[0184] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. 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, a daily dose selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg or 5 mg / kg to 10 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 dosein 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. Suitably the compound of the invention is admistered orally, for example in the form of a tablet, or capsule doasage form. The daily dose administered orally may be, for example a total daily dose selected from 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg or 25 mg to 500 mg. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

[0185] The compounds of the invention may be administered along with other active compounds as part of a treatment regime. The other active compounds may be administered simultaneously with, subsequently to or previously to the administration of the compounds of the invention. It may be that the pharmaceutical formulation comprising the compounds of the invention also comprises one or more other active compounds. The other active compounds may be anticancer, anti-inflammatory, antibacterial, antiviral, antiemetic, antithrombotic or compounds that alter the metabolism.

[0186] The other active compound may be an aminoglycoside. The other active compound may be an eRF1 modulator. The other active compound may be an inhibitor or suppressor of nonsense mediated decay. The other active compound may be an SMG1 kinase inhibitor. The other active compound may be a ribosomal binder.

[0187] The compounds of the invention may be administered in combination with an aminoglycoside. In some embodiments, the compounds of the invention may allow translational read-through of PTC mutations when administered in combination with a subeffective, sub-optimal, or sub-maximal amount of an aminoglycoside.

[0188] Aminoglycosides are compounds that have an amino-modified glycoside. Aminoglycosides are compounds that have an amino-modified glycoside. Aminoglycosides may allow translational read-through of PTC mutations. In some embodiments, when a compound of the invention is administered in combination with an aminoglycoside, the aminoglycoside may increase ribosomal read-through of mRNA transcripts carrying a PTC mutation of the cystic fibrosis CFTR channel.

[0189] Non-limiting examples of aminoglycosides include kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomicin, tobramycin, ELX-02, and pharmaceutically acceptable salts thereof.

[0190] It may be that administering a compound of the invention in combination with an aminoglycoside enhances PTC read-through. It may be that administering a compound of theinvention in combination with an aminoglycoside enhances PTC read-through whilst reducing the dose of aminoglycoside administered, relative to administration of the aminoglycoside alone, thereby reducing side effects, e.g. toxicity, associated with the aminoglycoside.

[0191] It may be that administering a compound of the invention in combination with an aminoglycoside increases the potency and / or beneficial effects of the aminoglycoside.

[0192] It may be that administering a compound of the invention in combination with an aminoglycoside reduces the dose of aminoglycoside required by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more, compared to administration of the aminoglycoside alone.

[0193] The compounds of the invention may be administered in combination with an eRF1 modulator, such as SRI-41315.

[0194] The compounds of the invention may be administered in combination with an inhibitor or suppressor of nonsense mediated decay, such as amlexanox, or NMD1.

[0195] The compounds of the invention may be administered in combination with an SMG1 kinase inhibitor, such as SMG1 L

[0196] The compounds of the invention may be administered in combination with an ribosomal binder, such as ZKN-013.

[0197] The compounds of the invention may be administered in combination with an antibody, for example a checkpoint inhibitor antibody. In some embodiments, the compounds of the invention may allow increased immune-cell recognition of cancer cells for use in the treatment of cancer, when administered in combination with a checkpoint inhibitor antibody. In some embodiments, the compounds of the invention may allow increased immune-cell recognition of cancer cells for use in the treatment of cancer, when administered in combination with a sub-effective, sub-optimal, or sub-maximal amount of a checkpoint inhibitor antibody.

[0198] Checkpoint inhibitor antibodies are a type of immunotherapy in oncology. Checkpoint inhibitor antibodies recognise and block different checkpoint proteins, for example, CTLA-4, PD-1 and PD-L1 , which triggers immune recognition and destruction of a tumour. Immune recognition may be enhanced when a compound of the invention is administered in combination with a checkpoint inhibitor antibody, wherein the compound promotes read- through of PTCs and increases the expression of neoantigens in cancer cells.

[0199] Non-limiting examples of checkpoint inhibitor antibodies include pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, avelumab, relatlimab, and ipilimumab.

[0200] It may be that administering a compound of the invention in combination with a checkpoint inhibitor antibody increases the potency and / or beneficial effects of the checkpoint inhibitor antibody.

[0201] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0202] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0203] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

[0204] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0205] The compounds of formula (I) can be made according to or analogously to General Schemes 1 to 2 and / or the following Examples.EXAMPLESTable of Abbreviations:NMR Methods:1H NMR spectra are recorded on Bruker AVANCE III HD 300, Bruker AVANCE NEO 400 or Bruker AVANCE III HD 400 spectrometers. Chemical shifts are denoted in ppm (5) relative to residual protonated solvent as an internal standard as described in, for example, Gottlieb et al. Journal of Organic Chemistry (1997) 62 7512. The splitting pattern for NMR spectra are denoted as follows: s (singlet), br (broad), d (doublet), t (triplet), m (multiplet) or combinations thereof. Coupling constants ( ) are designated in Hz and reported to one decimal place.Process for Preparation:Certain compounds of the invention may be synthesised according to the general methods disclosed herein. Certain compounds of the invention may be synthesised according to general schemes 1 to 2. Certain compounds of the invention may be synthesised according to or analogously to the syntheses provided in the examples.General Scheme 1General Scheme 1 illustrates a route to compounds of Formula (I) and is described in the following examples.Appropriately functionalised starting materials can be activated into a suitable leaving group X1(where X1= Cl, Br, OMs, OTs, OTf) by use of conditions well-known to those skilled in the art such as, for example, POC , POBrs, triflic anhydride, mesyl chloride or tosyl chloride in the presence of a suitable base if necessary (for example TEA, DIPEA), in a suitable solvent (for example DCM, THF) if necessary, with heating if required.Sequential displacement of X1can be achieved by reacting an amine in a cross-coupling reaction (where X1is, for example, Cl, Br, OTf) in the presence of a suitable catalyst (for example palladium^ I) acetate, Brettphos Pd G3, Pd2(dba)s), with a ligand if necessary (for example, Brettphos, XantPhos) with a suitable base (for example Na2COs, CS2CO3) in a suitable solvent (for example 1 ,4-dioxane, toluene, THF) with heating (conventional or by microwave irradiation) if required.Alternatively, sequential displacement of X1can be achieved by reacting an amine in a substitution reaction (where X1is, for example, Cl, OMs, OTs) conducted in the presence of a suitable base (for example TEA, KF, CsF, potassium terf-butoxide, Na2COs, CS2CO3) in a suitable solvent (for example 1 ,4-dioxane, DMSO, THF, NMP, or neat conditions) with heating (conventional or by microwave irradiation) if required.It will be well understood by those skilled in the art that either two coupling reactions, two substitution reactions or a mixture of coupling and substitution reactions may be required for the sequential, regioselective displacement of both X1groups.General Scheme 2General Scheme 2 illustrates a route to compounds of Formula (III) and is described in the following examples.A cross-coupling reaction of suitably functionalised starting materials (where X2is, for example, Cl, Br, I, OSO2CF3) with cyanamide can be conducted in the presence of a suitable catalyst (for example palladium^ I) acetate, Brettphos Pd G3, Pd2(dba)s), with a ligand if necessary (for example, Brettphos, XantPhos) with a suitable base (for example Na2COs, CS2CO3) in a suitable solvent (for example 1 ,4-dioxane, toluene, THF) with heating (conventional or by microwave irradiation) if required.Alternatively, a nucleophilic aromatic substitution (SNAr) reaction of suitably functionalised starting material (where X2is, for example, F, Cl, OMs, OTs) with cyanamide can be conducted in the presence of a suitable base (for example TEA, KF, CsF, potassium terf-butoxide, Na2COs, CS2CO3) in a suitable solvent (for example 1 ,4-dioxane, DMSO, THF, NMP, or neat conditions) with heating (conventional or by microwave irradiation) if required.The resultant cyano-cyanamide product can be cyclised by reaction with an appropriate nucleophile (for example an amine or hydroxylamine), using an appropriate base if necessary(for example triethylamine, DI PEA, potassium carbonate), in an appropriate solvent (for example DCM, DMSO, DMF, NMP, THF, 1,4-dioxane, ethanol, methanol) with heating (conventional or by microwave irradiation) if required.Purification Methods: Liquid chromatography-mass spectra (LCMS) are recorded using the following systems and running conditions:Purification by preparative HPLC (prep-HPLC) employs the following instruments and conditions:Separation by SFC employs the fo lowing instruments and conditions:Example 1 : A -(8-chloro-5-fluorochroman-4-yl)-5,7-dimethylpyrido[2,3-d]pyrimidine-5 2,4-diaminePreparation 1 - 5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diolTo a stirred mixture of 6-aminouracil (50.0 g, 393 mmol) in acetylacetone (200 mL) at room temperature was added PPA (90.5 g, 786 mmol). The resulting mixture was stirred at 100 °C 0 for 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with NaHCOs(aq) at 0 °C. The precipitated solids were collected by filtration and washed with water (2 x 300 mL). The solid was further purified by triturationwith MtBE (300 mL). This resulted in title compound as an off-white solid (38.0 g, crude). LCMS m / z = 192 [M+H]+Preparation 2 - 2,4-dichloro-5, 7-dimethylpyrido[2,3-d]pyrimidineTo a stirred mixture of 5,7-dimethylpyrido[2,3-c(]pyrimidine-2,4-diol (15.5 g, 81.1 mmol) in POC (155 mL) at 0 °C was added N, / -diethylaniline (60.5 g, 405 mmol) dropwise. The resulting mixture was stirred at 60 °C for 3 h. The resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The mixture basified to pH 8 with saturated NaHCCh (aq.). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (2:1) to afford the title compound as a yellow solid (9.8 g, 40.2%). LCMS: m / z = 228 [M+H]+Preparation 3 - 2-chloro-5, 7-dimethylpyrido[2,3-d]pyrimidin-4-amineA mixture of 2,4-dichloro-5,7-dimethylpyrido[2,3-c(]pyrimidine (5.60 g, 24.6 mmol) in ammonium hydroxide (85.0 mL) was stirred at room temperature for 1 h. The precipitated solids were collected by filtration and washed with water (3 x 10 mL). The solid was dried under vacuum to afford title compound as a brown solid (4.90 g, 95.5%). LCMS m / z = 209 [M+H]+Preparation 4 - N2-(8-chloro-5-fluorochroman-4-yl)-5, 7-dimethylpyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60 mg, 0.288 mmol) in ethyl alcohol (1 mL) at room temperature was added 8-chloro-5-fluorochroman-4- amine (173.69 mg, 0.864 mmol). The solvent was removed under reduced pressure and then the resulting mixture was stirred for 6-12 h at 110 °C. The solution was cooled to room temperature and purified by Agela MP-Flash200Libraryto afford the title compound as a solid (7.3 mg, 8.13%).1H NMR (300 MHz, DMSO-d6) 5 7.41 - 7.37 (m, 1 H), 7.26 (s, 1 H), 6.77 - 6.74 (m, 4H), 5.44 (d, J = 7.6 Hz, 1 H), 4.45 (d, J = 10.9 Hz, 1 H), 4.32 - 4.27 (m, 1 H), 2.67 (s, 3H), 2.40 (s, 3H), 2.27 - 2.04 (m, 2H). LCMSLibrary C: m / z = 374 [M+H]+.Example 2: A -(2-(1 H-imidazol-1 -yl)ethyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (50 mg, 0.240 mmol) in 1,4-Dioxane (2 mL) at room temperature was added N1,N1-dimethylethane-1,2- diamine (31.73 mg, 0.360 mmol) and CsF (108.72 mg, 0.72mmol). The resulting mixture was stirred for 16 h at 110 °C. The solution was cooled to room temperature and purified by Agela MP-Flash200 Library to afford the title compound as a solid (15.7 mg, 23.0%). LCMSLibrary A: m / z = 284 [M+H]+.Example 3 - Example 68These Examples were synthesised according to methods similar to those cited in the following table:Example 69: A / 3-(2-(1 H-imidazol-2-yl)ethyl)-6-methyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diaminePreparation 5 - Mixture of 1-methyl-3-oxo-4,5,6, 7-tetrahydro-3H-cyclopenta[c]pyridine-4- carbonitrile and 4-methyl-2-oxo-3,5, 6, 7-tetrahydro-2H-cyclopenta[b]pyridine-3-carbonitrile.To a mixture of 2-acetylcyclopentan-1-one (2.00 g, 15.9 mmol) and 2-cyanoacetamide (1.33 g, 15.9 mmol) in ethanol (20.0 mL) was added piperidine (1.35 g, 15.9 mmol). The mixture was stirred at 80 °C for 6 h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with ethanol (3 x 50 mL). The solid was dried under vacuum to afford the title compound (1 .67 g, crude, mixture of regioisomers) as a white solid. LCMS m / z = 175 [M+H]+.Preparation 6 - 3-chloro-1-methyl-6, 7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 2- chloro-4-methyl-6, 7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrileTo a solution of a mixture of 1-methyl-3-oxo-4,5,6,7-tetrahydro-3 / 7-cyclopenta[c]pyridine-4- carbonitrile and 4-methyl-2-oxo-3,5,6,7-tetrahydro-2 / 7-cyclopenta[b]pyridine-3-carbonitrile (800 mg, 4.59 mmol) in dioxane (15.0 mL) was added POCh (7.04 g, 45.9 mmol) dropwise at 0 °C. The resulting mixture was stirred at 100 °C for 6 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with CH2CI2 (20 mL) and quenched with sat. NaHCCh (aq.) at 0 °C. The resulting mixture was extracted with CH2CI2 (3 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (5:1) to afford a mixture of two isomers (770 mg, 87.0%) as a white solid. The mixture was separated by SFCAto afford 3-chloro-1-methyl-6,7-dihydro-5 / 7-cyclopenta[c]pyridine-4- carbonitrile (390 mg, R = 3 min) as a white solid and 2-chloro-4-methyl-6,7-dihydro-5 / 7- cyclopenta[b]pyridine-3-carbonitrile (250 mg, R = 4 min) as a white solid. LCMS m / z = 193 [M+H]+Preparation 7 - N-(4-cyano-1-methyl-6, 7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamideTo a solution of 3-chloro-1-methyl-6,7-dihydro-5 / 7-cyclopenta[c]pyridine-4-carbonitrile (360 mg, 1.87 mmol) and cyanamide (86.4 mg, 2.06 mmol) in dioxane (8.0 mL) were added BrettPhos Pd G3 (169 mg, 0.187 mmol), BrettPhos (100 mg, 0.187 mmol) and CS2CO3 (1.21g, 3.74 mmol). The mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through ashort pad of Celite. The pad was washed with CH2CI2 (3 x 50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAto afford the title compound (150 mg, 40.5%) as a white solid. LCMS m / z = 199 [M+H]+.Preparation 8 - N3-(2-(1H-imidazol-2-yl)ethyl)-6-methyl-8,9-dihydro-7H- cyclopenta[4, 5]pyrido[2, 3-d]pyrimidine- 1, 3-diamineTo a solution of / V-(4-cyano-1-methyl-6,7-dihydro-5 / 7-cyclopenta[c]pyridin-3-yl)cyanamide (100 mg, 0.50 mmol) and 2-(1 / 7-imidazol-2-yl)ethan-1 -amine dihydrochloride (185 mg, 1.00 mmol) in EtOH (5.00 mL) was added Et3N (102 mg, 1.00 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (26.4 mg, 16.9 %)as a light yellow solid.1H NMR (400 MHz, DMSO-cfe) 5 11.83 (s, 1 H), 7.13 - 6.59 (m, 4H), 6.53 (s, 1 H), 3.61 (q, J = 6.8 Hz, 2H), 3.31 - 3.24 (m, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.18 - 1.97 (m, 2H). LCMSAm / z = 310 [M+H]+.Example 70: A / 3-(3-(1 H-imidazol-1 -yl)propyl)-6-methyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-o(]pyrimidine-1, 3-diamineTo a solution of A / -(4-cyano-1-methyl-6,7-dihydro-5 / 7-cyclopenta[c]pyridin-3-yl)cyanamide (100 mg, 0.504 mmol) and 3-(1 / 7-imidazol-1-yl)propan-1 -amine (126 mg, 1.00 mmol) in EtOH (2.00 mL) was added Et3N (102 mg, 1.00 mmol). The resulting mixture was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (28.1 mg, 17.2 %) as a white solid.1H N MR (400 MHz, DMSO-cfe) 6 7.67 (s, 1 H), 7.23 (s, 1 H), 6.88 (s, 1 H), 6.78 - 6.27 (m, 3H), 4.03 (t, J = 6.9 Hz, 2H), 3.32 - 3.16 (m, 4H), 2.81 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.10 (p, J = 7.6 Hz, 2H), 1.97 (p, J = 6.8 Hz, 2H). LCMSAmlz = 324 [M+H]+.Example 71 : A / 3-(2-(1H-imidazol-1-yl)ethyl)-6-methyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-o(]pyrimidine-1, 3-diamineTo a solution of / V-(4-cyano-1-methyl-6,7-dihydro-5 / 7-cyclopenta[c]pyridin-3-yl)cyanamide (100 mg, 0.504 mmol) and 2-(1 / 7-imidazol-1-yl)ethan-1 -amine dihydrochloride (185 mg, 1.00 mmol) in EtOH (2.00 mL) was added Et3N (102 mg, 1.00 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCcto afford the title compound (33.8 mg, 21.6 %) as a white solid.1H NMR (400 MHz, DMSO-cfe) 5 7.58 (s, 1 H), 7.16 (s, 1 H), 6.86 (s, 1 H), 6.79 - 6.42 (m, 3H), 4.18 (t, J = 6.2 Hz, 2H), 3.59 (q, J = 6.1 Hz, 2H), 3.31 - 3.26 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.39 (s, 3H), 2.17 - 2.01 (m, 2H). LCMSAm / z = 310 [M+H]+.Example 72: A / 3-(2-(1 H-imidazol-4-yl)ethyl)-6-methyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-o(]pyrimidine-1,3-diamineTo a solution of A / -(4-cyano-1-methyl-6,7-dihydro-5 / 7-cyclopenta[c]pyridin-3-yl)cyanamide (100 mg, 0.504 mmol) in EtOH (2.00 mL) was added 2-(1 / 7-imidazol-4-yl)ethan-1 -amine hydrochloride (147 mg, 1.00 mmol, 2.00 equiv) and Et3N (102 mg, 1.00 mmol). The resulting mixture was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCcto afford the title compound (9.10 mg, 5.83 %) as a white solid.1H NMR (400 MHz, DMSO-cfe) 511.70 (s, 1 H), 7.53 (s, 1 H), 7.00 - 6.51 (m, 3H), 6.51 - 6.43 (m, 1 H), 3.52 (q, J = 6.9 Hz, 2H), 3.29 - 3.20 (m, 2H), 2.88 - 2.67 (m, 4H), 2.38 (s, 3H), 2.17 - 2.03 (m, 2H). LCMSAm / z = 310 [M+H]+.Example 73: A -(2-(1 H-imidazol-2-yl)ethyl)-5-methyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 9 - N-(3-cyano-4-methyl-6, 7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyanamideTo the solution of 2-chloro-4-methyl-6,7-dihydro-5 / 7-cyclopenta[b]pyridine-3-carbonitrile (230 mg, 1.194 mmol and cyanamide (55.2 mg, 1.31 mmol) in dioxane (5.0 mL) were added BrettPhos Pd G3 (108 mg, 0.119 mmol), BrettPhos (64.1 mg, 0.119 mmol) and CS2CO3 (778 mg, 2.39 mmol). The mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. Themixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with CH2CI2 (2 * 10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAto afford the title compound (120 mg, 50.7%) as a yellow solid. LCMS m / z = 199 [M+H]+.Preparation 10 N2-(2-( 1H-imidazol-2-yl)ethyl)-5-methyl-7, 8-dihydro-6H- cyclopenta[5, 6]pyrido[2, 3-d]pyrimidine-2, 4-diamineTo a stirred solution of A / -(3-cyano-4-methyl-6,7-dihydro-5 / 7-cyclopenta[b]pyridin-2- yl)cyanamide (100 mg, 0.50 mmol) and 2-(1 / 7-imidazol-2-yl)ethanamine dihydrochloride (186 mg, 1.01 mmol) in EtOH (3.00 mL) was added Et3N (102 mg, 1.01 mmol) at room temperature. The resulting mixture was stirred at 100 °C for overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCDto afford the title compound (15.1 mg, 9.37%) as an off-white solid.1H NMR (400 MHz, DMSO-cfe) 5 11.84 (br, 1 H), 7.11 - 6.36 (m, 5H), 3.67 - 3.54 (m, 2H), 2.93 - 2.79 (m, 6H), 2.58 (s, 3H), 2.08 - 1.97 (m, 2H). LCMSBm / z = 310 [M+H]+.Example 74: A -(3-(1 H-imidazol-1 -yl)propyl)-5-methyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2, 4-diamineA mixture of A / -(3-cyano-4-methyl-6,7-dihydro-5 / 7-cyclopenta[b]pyridin-2-yl)cyanamide (100 mg, 0.504 mmol) and 3-(imidazol-1-yl)propan-1 -amine (126 mg, 1.01 mmol) in EtOH (5.0 mL) was stirred at 100 °C for 5 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLCGto afford the title compound (83.7 mg, 51.3%) as white solid.1H NMR (400 MHz, DMSO-cfe) 6 7.68 (s, 1 H), 7.22 (s, 1 H), 6.88 (s, 1 H), 6.78 - 6.48 (m, 3H), 4.02 (t, J = 6.9 Hz, 2H), 3.25 (q, J = 6.4 Hz, 2H), 2.91 - 2.79 (m, 4H), 2.58 (s, 3H), 2.10 - 1.86 (m, 4H). LCMSAm / z = 324 [M+H]+Example 75: A -(2-(1 H-imidazol-1 -yl)ethyl)-5-methyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2, 4-diamineA mixture of A / -(3-cyano-4-methyl-6,7-dihydro-5 / 7-cyclopenta[b]pyridin-2-yl)cyanamide (100 mg, 0.504 mmol) and p-aminoethylimidazole (112 mg, 1.01 mmol) in EtOH (5.0 mL) was stirred at 100 °C for 5 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLCGto afford the title compound (60.4 mg, 38.7%) as white solid.1H NMR (400 MHz, DMSO-cfe) 5 7.59 (s, 1 H), 7.16 (s, 1 H), 6.86 (t, J = 1.2 Hz, 1 H), 6.77 (s, 2H), 6.56 (s, 1 H), 4.17 (t, J = 6.2 Hz, 2H), 3.58 (q, J = 6.1 Hz, 2H), 2.96 - 2.79 (m, 4H), 2.59 (s, 3H), 2.16 - 1.96 (m, 2H). LCMSAm / z = 310 [M+H]+Example 76: A -(2-( 1 H-imidazol-4-yl)ethyl)-5-methyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-c / ]pyrimidine-2,4-diamineTo a stirred mixture of A / -(3-cyano-4-methyl-6,7-dihydro-5 / 7-cyclopenta[b]pyridin-2- yl)cyanamide (100 mg, 0.504 mmol) and 2-(1 / 7-imidazol-4-yl)ethan-1 -amine hydrochloride (186 mg, 1.01 mmol) in EtOH (2.00 mL) was added Et3N (153 mg, 1.51 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCEto afford the title compound (86.5 mg, 55.4%) as a white solid.1H NMR (400 MHz, DMSO-cfe) 5 12.09 - 11.66 (m, 1 H), 7.71 - 7.45 (m, 1H), 6.89 (s, 1 H), 6.80 - 6.60 (m, 2H), 6.47 (s, 1 H), 3.63 - 3.45 (m, 2H), 3.01 - 2.66 (m, 6H), 2.58 (s, 3H), 2.13 - 1.94 (m, 2H). LCMSAm / z = 310 [M+H]+Example 77: Af-(3-((dimethylamino)methyl)phenyl)-5,7-dimethyl-1,8-naphthyridine-2,4- diaminePreparation 11 - ethyl 2-amino-4, 6-dimethylnicotinateTo a stirred solution of ethyl 3-amino-3-iminopropanoate hydrochloride (10.0 g, 60.0 mmol) in EtOH (90.0 mL) was added piperidine (15.3 g, 180 mmol) and pentane-2, 4-dione (9.01 g, 90.0 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE / EA (10 : 1) to afford the title compound as a light yellow solid (8.0 g, 68.6%). LCMS m / z = 195 [M+H]+.Preparation 12 - 5, 7-dimethyl-1,8-naphthyridine-2,4-diolTo a stirred solution of ethyl 2-amino-4,6-dimethylnicotinate (6.20 g, 31.9 mmol) in ethyl acetate (200 mL) was added NaH (8.94 g, 223 mmol, 60% in oil) in portions at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water / lce at 0 °C and extracted with EtOAc (100 mL x 3). The aqueous layer was acidified to pH 6 with AcOH. The precipitated solids were collected by filtration and washed with water (30 mL x 3). The solid was dried under vacuum. This resulted in the title compound as an off-white solid (4.8 g, 79.1%). LCMS m / z = 191 [M+H]+Preparation 13 - 2,4-dichloro-5, 7-dimethyl-1 ,8-naphthyridineTo a stirred mixture of 5,7-dimethyl-1 ,8-naphthyridine-2,4-diol (4.30 g, 22.6 mmol) in Toluene (130 mL) was added POCh (21.1 mL, 226 mmol) and DIEA (11.8 mL, 67.8 mmol) dropwise at 0 °C. The resulting mixture was stirred at 100 °C for 8 h. The mixture was allowed to cool down to room temperature. The resulting mixture was dropwise added into saturated NaHCOs(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (5:1) to afford the title compound as a red solid (3.7 g, 72.1 %). LCMS m / z = 227 [M+H]+.Preparation 14 - 2-chloro-5, 7-dimethyl-1,8-naphthyridin-4-amineA solution of 2,4-dichloro-5,7-dimethyl-1 ,8-naphthyridine (600 mg, 2.64 mmol) and CsF (1.20 g, 7.93 mmol) in NH3 H2O (20.0 mL) and dioxane (20.0 mL) was stirred at 100 °C for 34 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCDto afford 2- chloro-5,7-dimethyl-1 ,8-naphthyridin-4-amine as yellow solid (555 mg, crude) and 4-chloro- 5,7-dimethyl-1 ,8-naphthyridin-2-amine as yellow solid (430 mg, crude, isomer). LCMS m / z = 208 [M+H]+.Preparation 15 - N2-(3-((dimethylamino)methyl)phenyl)-5, 7-dimethyl-1,8-naphthyridine-2,4- diamineTo a stirred solution of 2-chloro-5,7-dimethyl-1 ,8-naphthyridin-4-amine (150 mg, 0.722 mmol) in dioxane (5.0 mL) at room temperature were added 3-[(dimethylamino)methyl]aniline (109mg, 0.722 mmol), Brettphos Pd G3 (65.5 mg, 72 pmol), Brettphos (38.8 mg, 72 pmol) and CS2CO3 (471 mg, 1.44 mmol). The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCFto afford the title compound (21.0 mg, 9.04%) as a yellow solid.1H NMR (400 MHz, DMSO- d6) 5 8.91 (s, 1 H), 8.11 (d, J = 7.96 Hz, 1 H), 7.48 (t, J = 1.9 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 6.81 (d, J = 7.52 Hz, 1 H), 6.76 (s, 1 H), 6.14 (s, 1 H), 6.02 (s, 2H), 3.35 (s, 2H), 2.75 (s, 3H), 2.44 (s, 3H), 2.16 (s, 6H). LCMScm / z = 322 [M+H]+.Biological testingLuciferase read-through assay

[0206] The read-through activity of compounds was assessed using the ADXC8 luciferase reporter cell line (generated as described in McElroy et al. PLoS Biology (2013), 11 , e1001593). Active compounds promote translational read-through of the R223X stop codon in the mutated luciferase gene which leads to generation of full-length luciferase in the compound-treated cells. The amount of luciferase is measured by adding a lysis buffer containing luciferin substrate and detecting luminescence using the following protocol:

[0207] ADXC8 cells in assay media (DMEM+10% FBS) were seeded into 96-well tissue culture treated white plates (Greiner) to a density of 13,000 cells per well and incubated for 24 hours at 37 °C in an atmosphere of 5% CO2. Compounds were solubilised in DMSO at a top concentration of 10 mM, serially diluted with assay media to 25 times final concentration and added to the plate to achieve a range of final concentrations of 100 pM to 0.045 pM in a final volume of 100 pL. Plates were incubated for a further 24 hours at 37 °C in an atmosphere of 5% CO2. Cells treated with 200 pM G418 (with 1% DMSO) were used as a positive control.

[0208] Cell viability and firefly luciferase activity were measured in the same assay wells. CellTiter-Fluor™ reagent was prepared as per manufacturer’s instructions (Promega E7120) and 20 pl of 5X CellTiter-Fluor™ reagent was added to all wells, briefly mixed by orbital shaking (300-500 rpm for ~30 seconds) and the plates incubated for 30-45 minutes at 37 °C in an atmosphere of 5% CO2. Cell viability was measured by monitoring fluorescence on a CLARIOstar® plate reader (BMG Labtech). Cells containing 1% DMSO were used as a positive control and cells with 400 pM Doxorubicine were used as negative control to define 100 and 0% respectively. ONE-Glo™ luciferase assay buffer (Promega E7120) was prepared according to manufacturer’s instructions and 100 pl of luciferase reagent was added to each well and the plate incubated at RT for 3 mins before measuring the luminescence on the CLARIOstar® plate reader (BMG Labtech). Cells treated with 200 pM G418 (with 1% DMSO)were used as a positive control and arbitrarily assigned a value of 100%. Cells treated with 1% DMSO were used as the negative control to define 0% response.

[0209] Concentration effect curves were analysed using non-linear regression using the CDD Vault from Collaborative Drug Discovery (Burlingame, CA). Where datapoints at the highest concentrations tested showed bell-shaped dose-response behaviour (due to cell toxicity confirmed by viability assay), they were removed from the analysis. The bottom and top of the curves were constrained to 0 and the maximum measured response respectively. From the fitted curves, the software derived C100% values (the concentration giving the same response as 200 pM G418) for each compound. The negative logarithm of C100% is reported as pC100% (Table 1). In addition to pC100% values, the maximum fold response relative to 200 pM G418 (Fold over Control) was also captured (Table 1). A pC100% categorisation of “- ‘ in Table 1 represents examples in which a pC100% response was not reached when assayed at a concentration of 100 pM. For Triamterene and pyrido[2,3-d]pyrimidine-2,4-diamine, a pC100% response was not reached when assayed at a concentration of 300 pM.

[0210] Table 1 - Luciferase Assay Data for Selected ExamplesKEY- pC 100% <4.0 # Fold over Ctrl > 0 < 1+ pC100% > 4.0 < 5.0 ## Fold over Ctrl >1 < 30++ pC100% >5.0 <6.0 ### Fold over Ctrl >30 < 60+++ pC100% >6.0 <7.0 #### Fold over Ctrl >60 < 90++++ pC100% > 7.0 < 8.0 ##### Fold over Ctrl >90+++++ pC100% >8.0

Claims

CLAIMS1 . A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof:whereinX is N or CR6;R1is independently selected from Co-Ce-alkylene-R1a;R1ais independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, naphthyl, a 9- or 10-membered bicyclic heteroaromatic ring system, and a 5- to 7- membered cycloalkyl or heterocycloalkyl ring fused to a phenyl ring; wherein the monocyclic heteroaromatic ring or phenyl ring may be fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring; wherein R1ais optionally substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 substituents, wherein a substituent attached to a cycloalkyl or heterocycloalkyl ring is selected from R9, and a substituent attached to a phenyl, naphthyl, or heteroaromatic ring is selected from R10;R2ais independently at each occurrence selected from H and C1-C4 alkyl;R2bis independently at each occurrence selected from H, C1-C4 alkyl, Ci-C4-haloalkyl, C0-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-Ci-C4-alkyl, S(O)-Ci-C4-alkyl, and S(O)2-Ci-C4-alkyl;R2cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 8- membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis phenyl, or heteroaryl, R2cis optionally substituted with from 1 to 5 R10groups;R2dis independently selected from NR7R8and OR7; or R2aand R2b, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups;R3is independently selected from H, cyano, Ci-C4-alkylene-NR7R8, NR7R8, Ci-C4-alkylene- OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2- C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene-R3c, 0-Co-C4-alkylene-R3c, and Co-C4-alkylene-R3c;R3cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R3cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R3cis optionally substituted with from 1 to 4 R9groups; and where R3cis phenyl or heteroaryl, R3cis optionally substituted with from 1 to 5 R10groups;R4is independently selected from H, halo, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- haloalkyl, 0-Co-C4-alkylene-R4c, and Co-C4-alkylene-R4c;R4cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis phenyl or heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups;R5is independently selected from H, halo, cyano, Ci-C4-alkylene-NR7R8, NR7R8, C1-C4- alkylene-OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, NR7-Co-C4-alkylene-R5c, O-C0-C4- alkylene-R5c, and Co-C4-alkylene-R5c;R5cis independently selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R5cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R5cis optionally substituted with from 1 to 4 R9groups; and where R5cis phenyl or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R3and R4together with the carbon atoms to which they are attached form a ring selected from: phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or e- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; or R4and R5together with the carbon atoms to which they are attached form a ring selected from: phenyl, Cs-Cy-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or e- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionallysubstituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups;R6is independently selected from H, halo, Ci-Ce-alkyl, and Ci-Ce-haloalkyl;R7is independently at each occurrence selected from H and C1-C4 alkyl;R8is independently at each occurrence selected from H, C1-C4 alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl;R9is independently at each occurrence selected from =0, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, and Ci-C3-alkylene-NR7R8;R9ais independently at each occurrence selected from Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, phenyl, 3- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R9ais cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups;R10is independently at each occurrence selected from halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, Ci-C3-alkylene-NR7R8, and Ci-Cs-alkylene-OR7; and wherein any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: Ci-C4-alkyl, Ci-C4-haloalkyl, oxo, halo, nitro, cyano, NRaRb, ORa, CRaRa-ORa, SRa, CO2Ra, C(O)Ra, CONRaRa, S(O)Ra, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and Ci-C4-alkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci-C4-alkyl.

2. A compound according to claim 1 , wherein X is N.

3. A compound according to claim 1 or claim 2, wherein R2aand R2bare each H.

4. A compound according to any one of claims 1 to 3, wherein R1Co-Ce-alkylene-R1a.

5. A compound according to any one of claims 1 to 4, wherein R1is R1a.

6. A compound according to any one of claims 1 to 5, wherein when R1ais a 5- to 7- membered heterocycloalkyl ring fused to a phenyl ring, the heteroatom(s) in R1, including any substituents therein, is / are independently selected from the group consisting of O and S.

7. A compound according to any one of claims 1 to 5, wherein R1ais independently selected from a 5- or 6-membered monocyclic heteroaromatic ring, phenyl, and a 9- or 10- membered bicyclic heteroaromatic ring system; wherein R1ais optionally substituted with Co- Ce-alkylene-R9aand / or from 1 to 6 substituents selected from R10.

8. A compound according to any one of claims 1 to 3, wherein R1iswhereinR11and R12are independently selected from H, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci- C4-alkylene-ORaand Ci-C4-alkylene-NRaRb, or R11and R12, together with the carbon to which they are attached, form a 5- to 7-membered cycloalkyl ring, optionally wherein the cycloalkyl ring is substituted with from 1 to 4 R9groups;R13is either absent or, R12and R13, together with the atoms to which they are attached, form a 5- to 7-membered cycloalkyl or heterocycloalkyl ring optionally substituted with from 1 to 6 R9; andRing C is independently selected from a 5- or 6-membered monocyclic heteroaromatic ring and phenyl, optionally wherein Ring C is fused to phenyl, a 5- or 6- membered monocyclic heteroaromatic ring, or a 5- to 7-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic ring system, optionally wherein Ring C or the bicyclic ring system is substituted with Co-Ce-alkylene-R9aand / or from 1 to 6 R10.

9. A compound according to any one of claims 1 to 8, wherein R3is H.

10. A compound according to any one of claims 1 to 9, wherein R3is Ci-C4-alkyl.

11. A compound according to any one of claims 1 to 10, wherein R4is H.

12. A compound according to any one of claims 1 to 10, wherein R4is Ci-C4-alkyl.

13. A compound according to any one of claims 1 to 12, wherein R5is R5c.

14. A compound according to any one of claims 1 to 13, wherein R5cis phenyl optionally substituted with from 1 to 5 R10groups.

15. A compound according to any one of claims 1 to 13, wherein R5cis 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups.

16. A compound according to any one of claims 1 to 12, wherein R5is H.

17. A compound according to any one of claims 1 to 12, wherein R5is Ci-C4-alkyl.

18. A compound according to claim 1 , wherein the compound of formula (I) is selected from:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, and one or more pharmaceutically acceptable excipients.

20. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use as a medicament.

21. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in the treatment of: a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.

22. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in the treatment of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Alport Syndrome, Dravet Syndrome, Aniridia,Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman- Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI,Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome and Retinitis Pigmentosa.

23. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in a method of treating conditions or disorders which are associated with a PTC mutation in a subject.

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