Inhibitory compounds

Abstract

The present invention relates to compounds of Formula (I), defined herein, that function as inhibitors of METTL1 enzyme activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which METTL1 activity is implicated.

Description

INHIBITORY COMPOUNDS FIELD OF THE INVENTION

[0001] The present invention relates to certain compounds that function as inhibitors of METTL1 activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which METTL1 activity is implicated. BACKGROUND OF THE INVENTION

[0002] The Methyltransferase 1 (METTL1) protein forms an RNA methyltransferase complex with WD repeat domain containing protein 4 (WDR4). The main substrates of the complex are transfer RNAs (tRNA), where METTL1 / WDR4 modify Guanosine to N7-Methylguanosine at position 46 (m7G46) in the variable loop, a site that is known to contribute to tertiary structure formation and stability in tRNAs (Kim et al., 1974; Robertus et al., 1974). METTL1 and WDR4 were first identified in the yeast Saccharomyces cerevisiae (named Trm8 and Trm82, respectively). They are highly conserved in eukaryotes and form a stable complex. Both proteins are required for the m7G46 modification of tRNAs, but the catalytic activity resides in METTL1, which harbors a SAM-binding and methyltransferase (MTase) domain (Alexandrov, Martzen and Phizicky, 2002).

[0003] Transfer RNAs are essential core components of the translation machinery of a cell. They provide the building blocks for protein synthesis within the ribosome as carriers of amino acids. tRNAs belong to so-called isoacceptor families, in which all members carry a specific amino acid. The specificity for the amino acid is determined through the recognition of a tRNA molecule by a cognate aminoacyl tRNA synthetase (aaRS), an enzyme which attaches an amino acid to the 3’ end of the tRNA molecule, a process called “charging” of tRNAs (Gomez and Ibba, 2020). Charged tRNAs are then engaging with the ribosome and actively translated messenger RNA (mRNA) to deliver the next amino acid to the growing polypeptide chain. The specificity of the amino acid incorporation into the newly synthesized protein is determined by the recognition of a so-called codon in the mRNA by the anticodon loop of the tRNA. A codon is a three-nucleotide sequence (triplet), which is complementary to a three-nucleotide anticodon sequence in a specific tRNA, which carries the corresponding amino acid. Hence, the abundance of specific anticodon-containing tRNAs (isodecoder families) can contribute to the efficiency and speed of translation of specific codon-containing mRNAs (Novoa and Ribas de Pouplana, 2012). Rapidly dividing cells such as cancer cells require elevated levels ofprotein synthesis. Often, an increase in mRNA translation rates can be attributed to the codon composition of these genes, whereby proliferation-promoting mRNAs harbor highly distinctive codon signatures compared to differentiation-promoting transcripts. In highly proliferative cells and tissues, the expression levels of specific tRNAs are often found to match the elevated expression of proliferation-associated genes, enabling optimal elongation rates and supporting cell growth (Gillen, Waldron and Bushell, 2021).

[0004] Post-transcriptional modifications of transfer RNAs have been known to exist for a long time. Hypomodification of tRNAs caused by mutations in tRNA modifying enzymes or in tRNAs themselves has been linked to human disease and developmental disorders (Suzuki, 2021). Mutations in WDR4 have been reported to cause various forms of microcephaly often combined with anomalies of the central nervous system and growth retardations (Shaheen et al., 2015; Braun et al., 2018). Patients with mutation in WDR4 had reduced levels of m7G46 on a subset of tRNAs, indicating that this modification is essential for full functionality of tRNAs, and that those tRNAs are required to support normal cell growth and development (Shaheen et al., 2015).

[0005] More recent studies have started to shed light onto the molecular mechanism of individual modifications in specific tRNA molecules. The m7G46 modification is required for stability of tRNAs. Downregulation of METTL1 / WDR4 protein levels by small interfering RNAs (siRNAs) or by CRISPR / Cas9-mediated genomic cleavage leads to the reduction of a subset of tRNAs, which have been shown to be substrates for METTL1 in human or mouse cell lines (Lin et al., 2018; Orellana et al., 2021). The reduced level of tRNAs subsequently leads to a decrease in translation rates of mRNAs, which are enriched in codons recognized by m7G- modified tRNAs. Conversely, increased METTL1 expression in tumor tissue or cancer cells leads to increased tRNA abundance and concomitantly higher expression of proteins, which are enriched in amino acids decoded by m7G-modified tRNAs (Dai et al., 2021; Orellana et al., 2021). Those highly expressed proteins are often associated with proliferation-related processes such as cell cycle regulation, translation, or DNA repair. Therefore, maintenance of tRNA expression levels to support optimal mRNA translation is crucial for cancer cell proliferation. Additionally, a second mechanism related to tRNA stability has been postulated whereby the m7G46 modification protects tRNA molecules from endonuclease-mediated cleavage and reduces the formation of tRNA fragments. CRISPR / Cas9-mediated downregulation of METTL1 increases the abundance of tRNA fragments, which in turn can repress translation initiation via inhibiting the mRNA cap-binding ability of the eukaryotic translation initiation factor eIF4F (García-Vílchez et al., 2023). In summary, stabilizing tRNA modifications such as m7G46 may significantly contribute to tumor growth by supporting optimal tRNA levels and preventing the inhibition of translation initiation or elongation.

[0006] METTL1 and WDR4 are often found over-expressed in tumor tissue when compared to normal tissue (Campeanu et al., 2021; Gao et al., 2022; He et al., 2022). Increased METTL1 / WDR4 expression in most cancer types but more specifically in bladder cancer, breast invasive carcinoma, colorectal cancer, glioblastoma, hepatocellular carcinoma, hepatic cholangiocarcinoma, lung adenocarcinoma, neuroblastoma, osteosarcoma, head and neck as well as esophageal squamous cell carcinoma, nasopharyngeal carcinoma, prostate cancer and hematopoietic cancers including acute myeloid leukemia (AML) seem to correlate with reduced overall survival rates and worse outcomes in those patients (Tian et al., 2019; Campeanu et al., 2021; Dai et al., 2021; Orellana et al., 2021; Wang et al., 2021; Ying et al., 2021; J. Chen et al., 2022; Han et al., 2022; Y. Huang et al., 2022; Z. Wang et al., 2023; García-Vílchez et al., 2023; Jiang et al., 2024). In addition, high expression levels of METTL1 / WDR4 also correlated with increased recurrence of cancerous and non-cancerous tumors such as head and neck squamous cell carcinoma and ameloblastoma (Chen et al., 2024; Wang et al., 2024). Analysis of gene expression data from cancer samples such as liver hepatocellular carcinoma and lung adenocarcinoma with elevated METTL1 expression indicates a positive correlation between METTL1 expression and genes involved in cell cycle control, replication and translation (Campeanu et al., 2021; Gao et al., 2022). This further corroborates the importance of a concerted gene expression program to maintain the high proliferation rates in cancer cells. Interestingly, gene set enrichment analysis in hepatocellular and prostate cancer revealed a potential inverse correlation of METTL1 expression with the Phosphatase and Tensin homolog (PTEN) pathway (Tian et al., 2019; García-Vílchez et al., 2023). PTEN is commonly found to be mutated in cancers and its status in tumor samples could serve as a selection marker for tumors with high METTL1 expression and dependency.

[0007] Additionally, the METTL1 gene is located in a region on Chromosome 12 (12q13-14), which is frequently amplified in cancer. More than 15% of Sarcoma tissue samples and approximately 13% of Glioblastoma samples analyzed in The Cancer Genome Atlas project (TCGA, PanCancer Atlas) harbor amplifications in the METTL1 locus, which are also commonly seen in other cancer types such as adrenocortical carcinoma, cholangiocarcinoma and non-small cell lung cancer (see figure 1). The METTL1 gene amplification status could therefore also serve as a stratification marker for tumors, which could be more dependent on its function.

[0008] The phenotypic consequences of METTL1 / WDR4 knock-down or knock-out are a reduction of cell proliferation, colony formation, migration and invasion capacity in several solid and leukemic cancer cell lines as well as a reduction of tumor formation in vivo.

[0009] Reduced protein expression of METTL1 and WDR4 significantly inhibited cell proliferation in hematologic cell lines of various blood cancer types including acute myeloidleukemia (AML), acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia, chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL), chronic lymphoblastic leukaemia (CLL) and diffuse large B-cell lymphoma (DLBCL) (Barbieri et al., 2017; Orellana et al., 2021; Zhao et al., 2024). At the molecular level, METTL1 / WDR4 plays a role in progression of AML by promoting protein biogenesis and cell cycle. Importantly, targeting METTL1 in primary murine AML cells induced strong inhibition of cell growth and colony formation capacity but had no effect in non-leukemic hematopoietic stem and progenitor cells (HSPCs) (Orellana et al., 2021) indicating that inhibition of METTL1 could selectively target cancer cells while not affecting non-transformed cell types.

[0010] Downregulation of METTL1 expression levels in cell lines of solid cancer types such as bladder cancer, hepatocellular carcinoma and intrahepatic cholangiocarcinoma resulted in reduced epidermal growth factor receptor (EGFR) protein expression levels and concomitant changes in downstream signaling cascades such as Phosphoinositide 3-kinase (PI3K), AKT Serine / Threonine Kinase 1 (AKT) and Mitogen-Activated Protein Kinase (MAPK) pathways leading to the reduced activation of effector kinases including extracellular signal‑regulated kinase (ERK). The compromised EGFR signaling pathways affected cell cycle progression, reduced cell proliferation and increased cell death in cancer cells (Chen et al., 2021; Dai et al., 2021; Ying et al., 2021; M. Huang et al., 2022). Those findings were further corroborated in head and neck squamous cell carcinoma (HNSCC), where the knock-down of METTL1 reduced activation of AKT and Mechanistic Target of Rapamycin Kinase (MTOR), both critical signaling proteins involved in the regulation of protein biogenesis, metabolism and cell cycle (J. Chen et al., 2022). In addition to affecting MTOR-mediated signaling in HNSCC, reducing METTL1 levels also increased autophagy pathways in esophageal squamous cell carcinoma and lung adenocarcinoma via MTOR target proteins, a process which can induce tumor suppression and cell death (Wang et al., 2021; Han et al., 2022). Additionally, METTL1 function seems to be required for WNT / β-catenin signaling in nasopharyngeal carcinoma, where the m7G modification in tRNAs is promoting the translation of key proteins in the pathway such as WNT family members WNT2 and WNT3A. In the absence of METTL1 and m7G modifications on tRNAs, the transcriptional coactivator of WNT-mediated signaling β- catenin is reduced, which in turn seems to negatively affect the process of Epithelial to Mesenchymal Transition (EMT), a critical step in tumor progression and metastasis (B. Chen et al., 2022). Two further studies also establish a link between the reduction of METTL1 / WDR4 activity and a reduced ability of cancer cells to undergo EMT, which is characterized by a switch between two members of the cadherin cell surface protein family. Upon knock-down of METTL1 or WDR4, N-cadherin protein expression is reduced while the tumor suppressor protein E-cadherin gets stabilized highlighting the potential that METTL1 / WDR4 inhibition orloss could reduce metastasis (Xia et al., 2021; Xie et al., 2022). In neuroblastoma, a common malignant childhood tumor characterized by N-MYC amplification, down-regulating METTL1 affected the translation of N-MYC target genes, corroborating the importance of METTL1 activity in driving oncogenic pathways (Y. Huang et al., 2022). In addition, METTL1 / WDR4 activity is required for cancer cell proliferation and tumor progression in glioblastoma, liposarcoma and melanoma, where the main mechanistic consequences of METTL1 knock- down is a reduction in tRNA levels (specifically of tRNA-Arg-TCT-4-1) and global translation, which leads to a block in cell cycle progression (Orellana et al., 2021).

[0011] In mouse embryonic stem cells (mESCs), METTL1 and WDR4 contribute to the expression of stem cell markers such as Nanog and Klf4, thereby maintaining the self-renewal and proliferation capacity of the mESCs and enabling accurate differentiation (Lin et al., 2018). Those findings have also been recapitulated in human induced pluripotent stem cell lines (hiPSCs), where a knock-down of METTL1 reduced the translation efficiency of stem cell marker genes resulting in cell cycle changes, reduced pluripotency, and aberrant differentiation to mesoderm (Deng et al., 2020). The attributes and gene expression profiles of ES cells have also been found in cells of poorly differentiated tumors and specific cancer types (Ben-Porath et al., 2008; Wong et al., 2008), which could potentially point towards a role of METTL1 / WDR4 or tRNA modifications and stability specifically in cancer stem cells.

[0012] In addition to its suggested role in primary tumor development, METTL1 and WDR4 seem to be also involved in conferring resistance to targeted cancer therapy, chemotherapy or radiation therapy in hepatocellular carcinoma (HCC), osteosarcoma, head and neck squamous cell carcinoma and nasopharyngeal carcinoma (Xia et al., 2021; B. Chen et al., 2022; Liao et al., 2022; M. Huang et al., 2022; Z. Wang et al., 2023; Chen et al., 2024). METTL1 protein levels were found to be upregulated after application of Ionizing Radiation (IR) in hepatocellular carcinoma. Over-expression of METTL1 forced the increased resistance to IR in cell lines and in mouse HCC models while the knock-down of METTL1 resulted in increased IR sensitivity. On the molecular level, METTL1 seems to promote non-homologous end-joining (NHEJ), a key pathway in the repair of double-strand DNA breaks induced by IR, by maintaining translation levels of the central NHEJ repair proteins DNA-PKcs and DNA ligase IV (Liao et al., 2022). Further to the IR resistance, increased expression of METTL1 or WDR4 also confers resistance to commonly used targeted therapy drugs in hepatocellular carcinoma, such as Lenvatinib and Sorafenib. Conversely, reduced expression of METTL1 or WDR4 in combination with these drugs resulted in a synergistic effect on cancer growth both in vitro and in vivo (Xia et al., 2021; M. Huang et al., 2022). A similar effect was observed in head and neck squamous cell carcinoma, where increased METTL1 protein levels were associated with resistance to the multitargeted tyrosine kinase inhibitor Anlotinib.Mechanistically, METTL1 promoted expression of proteins required for oxidative phosphorylation and energy metabolism, whose activity seemed to contribute to the resistance to Anlotinib (Chen et al., 2024). Further, in osteosarcoma and nasopharyngeal cancer models knock-down of METTL1 enhanced the sensitivity to chemotherapeutic agents Cisplatin, Docetaxel or Doxorubicin (B. Chen et al., 2022; Z. Wang et al., 2023) highlighting a putative future application of METTL1 inhibitors in combination with IR, targeted therapies or chemotherapy or as second line treatment in primary therapy-resistant tumors.

[0013] A further application for novel METTL1 inhibitors could be a combination with Immunotherapy. Recent studies have analyzed the composition of the microenvironment, especially immune cell infiltration, in tumors which developed in the absence or presence of functional METTL1 / WDR4. In a mouse model of intrahepatic cholangiocarcinoma (ICC), METTL1 knock-out reduced the infiltration of the tumor immune microenvironment (TIME) by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), a cell type that has been associated with generating an immunosuppressive TIME state in ICC. Additionally, an increased presence of CD4+ T cells was observed after METTL1 deletion. The ICC tumor growth reduction in conditional METTL1 knock-out mice could be enhanced by further treating animals with the Interleukin 8 Receptor beta (CXCR2) antagonist SB225002, which blocks a receptor in PMN-MDSCs and in combination with the immune checkpoint inhibitor anti-PD1 (Liu et al., 2022). In human prostate tumor tissue, METTL1 expression has been positively correlated with an increased infiltration of M2 type macrophages, which are associated with tissue growth and repair, and which support an immunosuppressive TIME state. Further studies using a prostate carcinoma mouse model showed that METTL1 knock-out induced an increased presence of M1 type macrophages, which are pro-inflammatory, and a mild increase in CD8+ cytotoxic T cells within these tumors, which was further accompanied by an increase in pro-inflammatory cytokines. Treatment of those METTL1-depleted mice with the immune checkpoint inhibitors anti-PD1 and anti-CTLA4 reduced the growth of prostate carcinomas compared to wild-type animals, indicating that a combination of METTL1 inhibition with immune checkpoint therapy could have an improved response rate in cancer therapy.

[0014] In addition to tRNAs, METTL1 / WDR4 have been implicated to methylate other RNA species, including mRNAs and microRNAs (miRNA) (Malbec et al., 2019; Pandolfini et al., 2019; Zhang et al., 2019; Liu et al., 2024). An m7G modification in the precursor of miRNA let- 7e-5p potentially reduces the formation of a local G-quadruplex structure thereby promoting its processing to the mature miRNA (Pandolfini et al., 2019). Internal (non-cap) m7G modification sites have been mapped in mRNAs by several orthogonal approaches. The m7G modification within coding exons seems to enhance the translation of those mRNAs independent of their codon composition (Malbec et al., 2019; Zhang et al., 2019) while m7Gsites in the 3′ untranslated regions (3′UTR) may render the modified transcripts less stable through IGF2BP protein-mediated degradation (Liu et al., 2024). Under cellular stress conditions, internal m7G modification in mRNAs seems to induce the accumulation of modified mRNAs in so-called stress granules via Quaking (QKI) RNA-binding proteins. The mRNA shuttling into stress granules may lead to decreased translation rates while protecting the mRNAs from degradation as part of a cellular adaption program to stress (Zhao et al., 2023). The expanded substrate repertoire of METTL1 / WDR4 could provide an additional layer of translational gene regulation in cancer. Inhibiting METTL1 could therefore potentially affect cancer growth via several different mechanisms.

[0015] Besides cancer, reducing METTL1 function could have a therapeutic effect in other proliferative disorders, which are characterized by a global increase in protein expression. Upon myocardial infarction or during cardiac hypertrophy-inducing processes, METTL1 protein and mRNA levels seem to be increased. This is accompanied by an enhanced proliferation capacity of cardiac myofibroblasts and an elevated protein expression and secretion phenotype, which leads to increased deposition of extracellular matrix (ECM) components and tissue fibrosis (L. Wang et al., 2023; Yu et al., 2024). A cardiac fibroblast- specific METTL1 knock-out led to reduced expression of ECM proteins, mildly reduced the symptoms of cardiac fibrosis and increased the heart function in a myocardial infarction mouse model, potentially indicating that reducing protein translation rates through inhibition of METTL1 could alleviate fibrosis and dampen scar tissue formation (L. Wang et al., 2023).

[0016] Therefore, METTL1 inhibitors may provide a novel therapeutic approach to a range of proliferative diseases.

[0017] Thus, METTL1 inhibitors may also provide a novel therapeutic approach to enhance an anti-tumour response.

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(2023) ‘QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism’, Cell, 186(15), pp.3208-3226.e27. Available at: https: / / doi.org / 10.1016 / j.cell.2023.05.047. SUMMARY OF THE INVENTION

[0019] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present invention provides a pharmaceutical composition as defined herein which comprises a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0021] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0022] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0023] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[0024] In a particular embodiment, the cancer is a haematologic cancer.

[0025] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cardiac fibrosis.

[0026] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the inhibition of METTL1 activity.

[0027] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in increasing or enhancing an anti-tumour immune response during immune-oncology therapy.

[0028] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in increasing or enhancing an anti-tumour response to radiotherapy (including ionizing radiation).

[0029] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the inhibition of metastasis in vivo.

[0030] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a proliferative condition.

[0031] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer. In a particular embodiment, the medicament is for use in the treatment of human cancers.

[0032] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cardiac fibrosis.

[0033] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of METTL1 activity.

[0034] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament foruse in increasing or enhancing an anti-tumour immune response during immune-oncology therapy.

[0035] In another aspect, the present invention provides a method of inhibiting METTL1 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0036] In another aspect, the present invention provides a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0037] In another aspect, the present invention provides a method of inhibiting metastasis in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0038] In another aspect, the present invention provides a method of increasing or enhancing an anti-tumour immune response during immune-oncology therapy, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0039] The present invention also provides a method of increasing or enhancing an anti- tumour response to radiotherapy in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein,

[0040] The present invention also provides a method of inhibiting metastasis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0041] In another aspect, the present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0042] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amountof a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0043] In another aspect, the present invention provides a method of treating cardiac fibrosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0044] In one aspect, the present invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents.

[0045] In one aspect, the present invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, for use in the treatment of cancer.

[0046] In one aspect, the present invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, for use in the treatment of cardiac fibrosis.

[0047] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt, as defined herein.

[0048] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0049] In another aspect, the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

[0050] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0051] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0052] 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 ordisplay clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0053] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0054] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “C1-6alkyl” includes C1-4alkyl, C1-3alkyl, propyl, isopropyl and t-butyl. A similar convention applies to other radicals, for example “phenyl(C1-6alkyl)” includes phenyl( C1-4alkyl), benzyl, 1-phenylethyl and 2-phenylethyl.

[0055] The term "(m-nC)" or “Cm-n”, or "(m-nC) group" or “Cm-n” used alone or as a prefix, refers to any group having m to n carbon atoms.

[0056] The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0057] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0058] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “C1-3alkylene” means a linear saturated divalent hydrocarbon radical of one to three carbon atoms or a branched saturated divalent hydrocarbon radical of three atoms, for example, methylene, ethylene, propylene, and the like.

[0059] The term “Cm-ncycloalkyl” means a hydrocarbon ring containing from m to n carbon atoms, for example “C3-6cycloalkyl” means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term “Cm-ncycloalkyl” also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbocyclic ring system(s). The term “Cm-ncycloalkyl” includes both monovalent species and divalent species. Monocyclic “Cm-ncycloalkyl” rings contain from about 3 to 12 (suitably from 3 to 8, most suitably from 5 to 6) ring carbon atoms. Bicyclic “Cm-ncycloalkyl” contain from 7 to 17 ring carbon atoms, suitably 7 to 12 ring carbon atoms. Bicyclic “Cm-ncycloalkyl” rings may be fused, spiro (e.g. spiro[3,3]heptane), or bridged ring systems (e.g. bicyclo[2.2.1]hept-2-ene and bicyclo[1.1.1]pentanyl).

[0060] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

[0061] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocyclyl includes both monovalent species and divalent species. Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7, most suitably from 5 to 6) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocycles contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituentsis, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0062] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane, quinuclidine, 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, bicyclo[3.2.1]octane, 7-oxabicyclo[2.2.1]hept-2-ene and 3-oxa-8-azabicyclo[3.2.1]octane .

[0063] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0064] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0065] In the present invention “heteroaryl” also covers rings such as pyridones (e.g. 2- pyridonyl), pyrazinones and pyrimidinones (e.g.4-pyrimidonyl).

[0066] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0067] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0068] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0069] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0070] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0071] The term “aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0072] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0073] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0074] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically. Compounds of the invention

[0075] In one aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof:wherein: Ring A is (3-12C)cycloalkyl or 4- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1, OC(O)RA1, C(O)N(RA1)RA2, N(RA1)C(O)RA2; wherein RA1and RA2are each independently selected from hydrogen or (1-4C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by (1-4C)alkyl; and any (1-6C)alkyl in a substituent on Ring A is optionally further substituted by one or more of halo, cyano, (1-4C)alkoxy, hydroxy or NH2; wherein Ring A is optionally fused to a phenyl ring or a 5- or 6-membered heteroaryl ring, wherein the phenyl ring or a 5- or 6-membered heteroaryl ring may in turn be optionally substituted by one or more substituents selected from from (1-6C)alkyl, halo, (1-6C)- haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-4C)alkyl; Ring B is a 5 to 10-membered aryl or heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis a group of the formula: XB-YB-ZBwherein XBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RXaand RXbis independently selected from hydrogen or (1-2C)alkyl;YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, -N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1-2C)alkyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, aryl (e.g. phenyl), heterocyclyl (including a 4 to 7 membered monocyclic heterocyclic or a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), heteroaryl (including a monocyclic or bicyclic heteroaryl ring system), C3-8cycloalkyl(1-4C)alkyl, aryl(1-4C)alkyl, heterocyclyl(1-4C)alkyl or heteroaryl(1- 4C)alkyl; and wherein ZBis optionally further substituted by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-6C)alkyl or (1-6C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl; R1aand R1bare independently selected from hydrogen, (1-2C)alkyl, halo, (1-2C)haloalkyl, with the proviso that at least one of R1aand R1bis not hydrogen; R3a, R3b, R4aand R4bare each independently selected from hydrogen, halo or methyl; R5and R7are each independently selected from hydrogen, halo, hydroxy, methyl or methoxy; R6is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; R8is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; wherein any one or more nitrogen atoms in the compound of Formula (I) is optionally in the form of an N-oxide.

[0076] In another aspect, the present invention relates to compounds of the formula (I), or a pharmaceutically acceptable salt thereof:wherein: Ring A is (3-12C)cycloalkyl or 4- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1, OC(O)RA1, C(O)N(RA1)RA2, N(RA1)C(O)RA2; wherein RA1and RA2are each independently selected from hydrogen or (1-4C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by (1-4C)alkyl; and any (1-6C)alkyl in a substituent on Ring A is optionally further substituted by one or more of halo, cyano, hydroxy or NH2; Ring B is a 5 to 10-membered aryl or heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis a group of the formula: XB-YB-ZBwherein XBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RXaand RXbis independently selected from hydrogen or (1-2C)alkyl; YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, -N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1-2C)alkyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, aryl (e.g. phenyl), heterocyclyl (including a 4 to 7 membered monocyclic heterocyclic or a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), heteroaryl (including a monocyclic or bicyclic heteroaryl ring system), C3-8cycloalkyl(1-4C)alkyl, aryl(1-4C)alkyl, heterocyclyl(1-4C)alkyl or heteroaryl(1- 4C)alkyl; and wherein ZBis optionally further substituted by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-6C)alkyl or (1-6C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl; R1aand R1bare independently selected from hydrogen, (1-2C)alkyl, halo, (1-2C)haloalkyl, with the proviso that at least one of R1aand R1bis not hydrogen; R3a, R3b, R4aand R4bare each independently selected from hydrogen, halo or methyl; R5and R7are each independently selected from hydrogen, halo, hydroxy, methyl or methoxy; R6is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; R8is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; wherein any one or more nitrogen atoms in the compound of Formula (I) is optionally in the form of an N-oxide.

[0077] Particular compounds of the invention include, for example, compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of and any associated substituent groups has any of the meanings defined hereinbefore or in any one of paragraphs (1) to (57) hereinafter:- (1) Ring A is selected from (5-10C)cycloalkyl or 5- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1or C(O)N(RA1)RA2wherein RA1and RA2are each independently selected from hydrogen or (1-3C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by (1- 2C)alkyl.(2) Ring A is selected from (5-8C)cycloalkyl (including monocyclic and bridged, fused, or spirocyclic cycloalkyl) or 5- to 8-membered heterocyclyl (including monocyclic and bridged, fused, or spirocyclic heterocyclyl); wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, oxo, cyano, NRA1RA2or ORA1, wherein RA1and RA2are each independently selected from hydrogen or (1-2C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by methyl. (3) Ring A is as defined in either item a) or b) below: a) Ring A is selected from:,wherein any available carbon atom in the above rings in lists a) and b) may be optionally substituted on any available carbon atom by one or more substituents as defined herein; and may be optionally substituted on any available nitrogen atom by methyl; and wherein if Ring A is selected from list a), then the atom to which Ring A is attached to in Ring B is a carbon atom. (3a) Either: a) Ring A is selected from:wherein any available carbon atom in the above rings may be optionally substituted on any available carbon atom by one or more substituents as defined anywhere herein; and may be optionally substituted on any available nitrogen atom by methyl; and wherein if Ring A is selected from list a), then the atom to which Ring A is attached to in Ring B is a carbon atom. (3b) Ring A is selected from the options as defined in paragraph (3a) above; wherein any available non-aromatic carbon atom in a ring defined in paragraph (3a) may be optionally substituted by one or more substituents selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkyl, (1-2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; and any available aromatic carbon atom in a ring defined in paragraph (3a) may be optionally substituted by a substituent independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-3C)alkyl. (3c) Ring A is selected from the options as defined in paragraph (3a) above;wherein any available non-aromatic carbon atom in a ring defined in paragraph (3a) above may be optionally substituted by one or more substituents independently selected from (1-2C)alkyl, (1-2C)alkoxy, halo, (1-2C)haloalkyl, oxo, cyano, ORA1, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-2C)alkyl; wherein any (1-3C)alkyl or (1-3C)alkoxy is optionally substituted by one or more substituents selected from fluoro, cyano, (1- 2C)alkoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; and any available aromatic carbon atom in a ring defined in paragraph (3a) above may be optionally substituted by a substituent independently selected from (1- 2C)alkyl, halo, (1-2C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)ORA3or C(O)N(RA3)RA4, wherein RA3and RA4are each independently selected from hydrogen or (1-2C)alkyl. (3d) Ring A is selected from the options as defined in paragraph (3a) above; wherein any available non-aromatic carbon in a ring defined paragraph (3a) may be optionally substituted by one or more substituents selected from fluoro, chloro, hydroxy, oxo, (1-2C)alkyl, (1-2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, methoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; and any available aromatic carbon atom in a ring defined in paragraph (3a) may be optionally substituted by a substituent selected from methyl, fluoro, cyano, NRA3RA4or ORA3, wherein RA3and RA4are each independently selected from hydrogen or methyl. (4) Ring A is selected from:. (5a) Ring A is selected from:(6) Ring A is:.(7) Ring A is:. (8) Ring B is selected from phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis as defined anywhere herein; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl. (9) Ring B is selected from: i) a group with the formula:, wherein: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B3 is selected from N or CRB3; B4is selected from S, O, N, NRB4Nor CRB4; and B5is selected from N or CRB5; with the proviso that no more than three of the atoms which make up the ring formed by B1, B2, B3, B4and B5are a heteroatom; wherein: each of RB2, RB3, RB4and RB5are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RB2Nand RB4Nare selected from hydrogen or (1-2C)alkyl; ii) a group with the formula:, wherein C2is selected from N or CRC2; C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; C6is selected from N or CRC6; with the proviso that no more than two of C2,C3,C4,C5or C6are nitrogen; wherein each of RC2, RC3, RC4and RC5are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1- 4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl or a 4- to 7 membered heterocyclyl; iii) a group with a formula selected from:wherein: D2is selected from N or CRD2; D3is selected from N or CRD3; D4is selected from N or CRD4; D5is selected from N or C; D6is selected from S, O, N, NRD6Nor CRD6;D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; RN3is selected from hydrogen or (1-2C)alkyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising D2, D3, D4, D5, D6, D7, D8and D9are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O) D5, D6,D7, D8and D9are a heteroatom; wherein: each of RD2, RD3, RD6and RD8are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RD4and RD7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; and RD6Nand RD8Nare selected from hydrogen or (1-4C)alkyl; iv) a group with the formula:wherein: Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that no more than four of the atoms which make upthe bicyclic ring comprising Y1, Y2, Y3, Y4, Y5, Y6,Y7, Y8and Y9are a heteroatom; wherein: each of RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; RY2Nand RY3Nare each independently selected from hydrogen or (1-4C)alkyl; and RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; or v) a group with a formula selected from:wherein: Z2is selected from N or CRZ2; Z3is selected from N or CRZ3; Z4is selected from N or CRZ4; Z5is selected from N or C; Z6is selected from N or CRZ6; Z7is selected from N or CRZ7; Z8is selected from N or CRZ8; Z9is selected from N or CRZ9; Z10is selected from N or C; RN7is selected from hydrogen or (1-2C)alkyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6,Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, N(RN7), C(O), Z8, Z9and Z10are a heteroatomwherein: each of RZ2, RZ3, RZ4, RZ6and RZ9are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy; and RZ7and RZ8are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (10) Ring B is selected from: i) a group with the formula:, wherein: B1, B2, B4and B5are as defined anywhere herein; ii) a group with the formula:wherein C2, C4, C5, C6, RC2, RC3, RC4, RC5and RC6, are as defined anywhere herein; iii) a group with the formula:wherein D2, D4, D5, D7, D8, D9and RN3are as defined anywhere herein; iv) a group with the formula:wherein Y1, Y2, Y4, Y5, Y7, Y8and Y9are as defined anywhere herein; v) a group with a formula selected from:wherein Z2, Z4, Z5, Z8, Z9, Z10and RN7are as defined anywhere herein. (11) Ring B is selected from: i) a group with the formula:, wherein: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B4is selected from S, O, N, NRB4Nor CRB4; and B5is selected from N or CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure;ii) a group with the formula:wherein: C2is selected from N or CRC2; C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; and C6is selected from N or CRC6; with the proviso that no more than one of C2, C3, C4, C5or C6is nitrogen; iii) a group with the formula:wherein: D2is selected from N or CRD2; D3is selected from N; D4is selected from N or CRD4; D5is selected from N or C; D6is selected from S, O, N, NRD6Nor CRD6; D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8;D9is selected from N or C; and RN3is selected from hydrogen or methyl with the proviso that no more than four of the atoms which make up the bicyclic ring comprising D2, D3, D4, D5, D6,D7, D8and D9are a heteroatom, and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O) D5, D6,D7, D8and D9are a heteroatom; iv) a group with the formula:Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; and Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, Y6, Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; or v) a group with a formula selected from:Z2is CRZ2; Z3is selected from N or CRZ3; Z4is selected from N or CRZ4; Z5is C; Z6is selected from N or CRZ6; Z7is selected from N or CRZ7; Z8is CRZ8; Z9is CRZ9; and Z10is C; RN7is selected from hydrogen or methyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6,Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, N(RN7), C(O), Z8, Z9and Z10are a heteroatom; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8and RZ9are independently as defined herein. (12) Ring B is selected from: i) a group with the formula:, wherein: B1is selected from N or C; B2is CRB2; B4is selected from S, NRB4Nor CRB4; and B5is CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; ii) a group with the formula:wherein: C2is selected from N or CRC2; C4is CRC4; C5is selected from N or CRC5; and C6is CRC6; with the proviso that no more than one of C2, C4, C5or C6is nitrogen; iii) a group with the formula:wherein: D2is CRD2; D4is CRD4; D5is selected from C; D6is selected from S, O or N; D7is selected from N, CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; and RN3is selected from hydrogen or (1-2C)alkyl with the proviso that the 9-membered bicyclic ring comprising D2, N, D4, D5, N, D7, D8and D9comprises no more than 4 heteroatoms in the ring structure; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O) D5, D6, D7, D8and D9are a heteroatom; iv) a group with the formula:Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; and Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, Y3, Y4, Y5, N, Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; v) a group with the formula:Z2is CRZ2; Z3is CRZ3; Z4is CRZ4; Z5is N or C; Z6is CRZ6; Z7is CRZ7; Z8is CRZ8; Z9is CRZ9; Z10is C; and RN7is selected from hydrogen or (1-2C)alkyl;with the proviso that no more than four of the atoms which make up the bicyclic ring structures defined in item v) are a heteroatom; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8, RZ9, RN3and RN7are independently as defined anywhere herein. (13) Ring B is selected from: i) a group with a formula selected from:ii) a group with a formula selected from:iii) a group with a formula selected from:,iv) a group with a formula selected from:v) a group with the formula selected from:wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8, RZ9, RN3and RN7are independently as defined anywhere herein. (14) Ring B is selected from: i) a group with a formula selected from:, wherein:RB2is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1- 4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; RB4is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1- 4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; and RB5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1- 4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; ii) a group with a formula selected from:wherein: RC2is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC3is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC4is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl or a 4- to 7 membered heterocyclyl;iii) a group with a formula selected from:wherein:RD2, RD3and RD8are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RD4is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; and RD8Nis selected from hydrogen or (1-4C)alkyl; iv) a group with a formula selected from:wherein:RY2is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RY5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1- 4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; and RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; and RY8is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl (e.g. CF3) or fluoromethoxy (e.g. OCF3); v) a group with the formula selected from:wherein: each of RZ2, RZ3, RZ6and RZ9are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; RZ4, RZ7and RZ8are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.(15) Ring B is selected from: i) a group with a formula selected from:, wherein: RB2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RB4is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; and RB5is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; ii) a group with a formula selected from:wherein: RC2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC3is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC4is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC5is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy, (4-6C)cycloalkyl or a 5- to 6 membered heterocyclyl;iii) a group with a formula selected from:wherein: RD2is selected from hydrogen or halo (e.g. fluoro or chloro); RD3and RD8are independently selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RD4is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; or iv) a group with a formula selected from:RY2independently selected from hydrogen or halo (e.g. fluoro or chloro); RY5independently selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; and RY8independently selected from hydrogen or halo (e.g. fluoro or chloro); or v) a group with the formula selected from:each of RZ2, RZ3, RZ6and RZ9are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RZ4is selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; RZ6is selected from hydrogen, halo, hydroxy, methyl, methoxy or fluoromethyl (e.g. CF3); and one of RZ7and RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3, and the other is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (16) Ring B is selected from: i) a group with a formula selected from:, wherein: RB2is selected from hydrogen or halo; RB4is selected from hydrogen or halo; and RB5is selected from hydrogen or halo; ii) a group with a formula selected from:wherein: RC2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC3is selected from hydrogen or halo RC4is selected from hydrogen, halo or methoxy; RC5is selected from hydrogen, halo or methoxy; and RC6is selected from hydrogen, halo or 6 membered heterocyclyl; iii) a group with a formula selected from:wherein: RD2is selected from hydrogen or halo; RD3is selected from hydrogen or halo; RD8is selected from hydrogen or halo; RD4is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano or methyl; and RD7is selected from hydrogen, halo, cyano or a group RB; iv) a group with a formula selected from:wherein: RY2is selected from hydrogen or halo; RY5is selected from hydrogen or halo; RY8is selected from hydrogen or halo; and RY7is selected from hydrogen, halo, cyano or a group RB; or v) a group with the formula selected from:wherein: RZ2is selected from hydrogen or halo; RZ3is selected from hydrogen or halo; RZ4is selected from hydrogen, fluoro, bromo, iodo, cyano or methyl; RZ6is selected from hydrogen, halo or hydroxy; and one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; and RZ9is selected from hydrogen or halo; wherein RBis as defined anywhere herein. (17) Ring B is a group with a formula selected from:wherein RB2, RB4and RB5are as defined anywhere herein. (18) Ring B is a group with a formula selected from:wherein RC2, RC4, RC5and RC6are as defined anywhere herein. (19) Ring B is a group with a formula selected from:wherein: RD2, RD3, RD4, RD7and RD8and RD8Nare as defined anywhere herein. (20) Ring B is a group with a formula selected from:wherein RY2, RY5, RY7and RY8are as defined anywhere herein. (20a) Ring B is a group with a formula selected from:wherein each of RZ2, RZ3, RZ4, RZ6, RZ7, RZ8and RZ9are as defined anywhere herein. (21) Ring B is selected from:,wherein: RC3, RC4, RC5and RC6are as defined anywhere herein; RD4, RD7and RY7are independently selected from hydrogen, halo, cyano or a group RB,one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; wherein RBis as defined anywhere herein. (22) Ring B is selected from:wherein: RC3, RC4, RC5and RC6are as defined anywhere herein; RD4, RD7and RY7are independently selected from hydrogen, halo, cyano or a group RB, one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; wherein RBis as defined anywhere herein. RD4and RZ4are selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; preferably RZ4is selected from hydrogen, fluoro, bromo, iodo, cyano or methyl;RD7and RY7are selected from hydrogen, halo, cyano or a group RB; one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; wherein RBis as defined anywhere herein.wherein RD7are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (24) RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are each independently selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl (e.g. CF3) or fluoromethoxy; and RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare selected from hydrogen or methyl; (24a) RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RZ2, RZ3, RZ6and RZ9RY8are independently selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy, (4-6C)cycloalkyl or a 5- to 6 membered heterocyclyl; and RB2N, RB4NRD6N, RD8N, RY2N, RY3N, RN3and RN7are selected from hydrogen or methyl. (25) RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen or halo; and RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare independently selected from hydrogen or methyl. (25a) RB2, RB3, RB4, RB5RC2, RC3, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RZ2, RZ3, RZ6and RZ9are independently selected from hydrogen or halo;RC4and RC5are independently selected from hydrogen, halo or methoxy, preferably hydrogen or methoxy; RC6is selected from hydrogen, halo or a 6 membered monocyclic heterocyclyl; and RB2N, RB4NRD6N, RD8N, RY2N, RY3N, RN3and RN7are independently selected from hydrogen or methyl. (26) RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are hydrogen; RD2is selected from hydrogen or halo, e.g. fluoro, chloro or bromo; and RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare independently selected from hydrogen or methyl. (26a) RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RZ2, RZ3, RZ6and RZ9are hydrogen; RD2is selected from hydrogen or halo, e.g. fluoro, chloro or bromo; and RB2N, RB4NRD6N, RD8N, RY2N, RY3N, RN3and RN7are independently selected from hydrogen or methyl. (27) RD4and and RZ4are selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (28) RD4and and RZ4are selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy. (29) RD4and RZ4are selected from hydrogen, fluoro, bromo, iodo, cyano or methyl. (29a) RD4and RZ4is hydrogen. (30) RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (30a) RD7is hydrogen or NH2. (31) RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (31a) RZ7is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3) and RZ8is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (31b) RZ7is hydrogen and RZ8is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.(31c) RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3) and RZ7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (31d) RZ8is hydrogen and RZ7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein. (32) RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RXaand RXbis independently selected from hydrogen or methyl; YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -N(RY1)-, -N(RY1)- C(O)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclic ring system, 5 to 9-membered spirocyclic heterocyclic ring system, or 5 to 9-membered bridged heterocyclic ring system or a monocyclic or bicyclic heteroaryl ring system, phenyl, 5- to 10-membered heteroaryl, C3-8cycloalkyl(1-4C)alkyl, phenyl(1-4C)alkyl, (4 to 9- membered)heterocyclyl(1-4C)alkyl or (4 to 9-membered)heteroaryl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1or C(O)ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; wherein if XBand YBare absent, then ZBis not hydrogen. (33) RBis is a group of the formula: XB-YB-ZBwherein XBis absent or [CH2]n, wherein n is an integer from 1 to 2; YBis absent or selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl;ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclyl, 5 to 9-membered spirocyclic heterocyclyl, 5 to 9-membered bridged heterocyclyl, a monocyclic or bicyclic heteroaryl, phenyl, C3-8cycloalkyl(1-4C)alkyl, (4 to 7 membered monocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered fused bicyclic)heterocyclyl(1- 4C)alkyl, (5 to 9-membered spirocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered bridged)heterocyclyl(1-4C)alkyl, (monocyclic or bicyclic)heteroaryl(1-4C)alkyl, or phenyl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, oxo, cyano, hydroxy, NH2or methyl; and wherein if XBand YBare absent, then ZBis not hydrogen. (34) RBis is a group of the formula: XB-YB-ZBwherein XBis absent or -[CH2]-; YBis absent or selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclyl, 5 to 9-membered spirocyclic heterocyclyl, 5 to 9-membered bridged heterocyclyl, a monocyclic or bicyclic heteroaryl, phenyl, C3-8cycloalkyl(1-4C)alkyl, (4 to 7 membered monocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered fused bicyclic)heterocyclyl(1- 4C)alkyl, (5 to 9-membered spirocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered bridged)heterocyclyl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; wherein if XBand YBare absent, then ZBis not hydrogen.(35) RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CH2]; YBis selected from -N(RY1)- or -N(RY1)-C(O)- wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, C3-8cycloalkyl(1-4C)alkyl or 4 to 7 membered monocyclic heterocyclyl(1- 4C)alkyl; and wherein ZBis optionally substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl. (35a) RBis a group with a formula selected from:,,(37) R1aand R1bare independently selected from hydrogen, methyl, fluoro or fluoromethyl, with the proviso that at least one of R1aand R1bis not hydrogen. (38) R1aand R1bare independently selected from hydrogen or methyl, with the proviso that at least one of R1aand R1bis not hydrogen. (39) R1ais hydrogen and R1bis methyl. (40) R1ais methyl and R1bis hydrogen. (41) R3aand R3bare each independently selected from hydrogen or halo; (42) One of R3aand R3bis hydrogen and the other is selected from hydrogen or halo. (43) R3aand R3bare hydrogen; (44) R4aand R4bare each independently selected from hydrogen or halo; (45) One of R4aand R4bis hydrogen and the other is selected from hydrogen or halo. (46) R4aand R4bare hydrogen; (47) R5is selected from hydrogen, halo or methoxy; (48) R5is hydrogen. (49) R6is selected from hydrogen, hydroxy, methyl, halo, methoxy, fluoromethyl or fluoromethoxy. (50) R6is selected from hydrogen, fluoro, chloro or fluoromethyl (e.g. CF3, CHF2, or CH2F).(51) R6is selected from fluoro, chloro or trifluoromethyl. (51a) R6is selected from chloro or trifluoromethyl. (52) R7is selected from hydrogen, halo, hydroxy or methoxy; (53) R7is hydrogen or hydroxy. (54) R7is hydrogen (55) R8is selected from hydrogen, hydroxy, methyl, halo, methoxy, fluoromethyl or fluoromethoxy. (56) R8is selected from hydrogen, fluoro, chloro or trifluoromethyl. (57) R8is selected from hydrogen or chloro. (57a) R8is chloro. (58) Ring A is selected from (5-10C)cycloalkyl or 5- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-3C)alkyl; wherein any (1- 3C)alkyl is optionally further substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and Ring A may be optionally substituted on any available nitrogen atom by (1- 2C)alkyl; wherein Ring A is optionally fused to a phenyl ring or a 6-membered heteroaryl ring, wherein each of which may in turn be optionally substituted by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-3C)alkyl. (59) Ring A is selected from (5-8C)cycloalkyl (including monocyclic and bridged, fused, or spirocyclic cycloalkyl) or 5- to 8-membered heterocyclyl (including monocyclic, bridged, fused, or spirocyclic heterocyclyl); wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, oxo, cyano, ORA1, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-2C)alkyl; wherein any (1-2C)alkyl is optionally substituted by one or more substituents selected from fluoro, cyano, (1- 2C)alkoxy or hydroxy; and Ring A may be optionally substituted on any available nitrogen atom by methyl; wherein Ring A is optionally fused to a phenyl ring which may in turn be optionally substituted by one or more substituents independently selected from (1-2C)alkyl,halo, (1-2C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)ORA3or C(O)N(RA3)RA4, wherein RA3and RA4are each independently selected from hydrogen or (1-2C)alkyl. (60) Ring A is selected from (5-8C)cycloalkyl (including monocyclic and bridged, fused, or spirocyclic cycloalkyl) or 5- to 8-membered heterocyclyl (including monocyclic, bridged, fused, or spirocyclic heterocyclyl); wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from fluoro, chloro, hydroxy, oxo, (1-2C)alkyl, (1- 2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1- 2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, methoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; wherein Ring A is optionally fused to a phenyl ring which may in turn be optionally substituted by one or more substituents selected from methyl, fluoro, cyano, NRA3RA4or ORA3, wherein RA3and RA4are each independently selected from hydrogen or methyl. (61) One of the following applies: a) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Ring A1, A2, A3 or A4 are selected from saturated or partially saturated monocyclic, bridged, fused, or spirocyclic (5-10C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 5- to 10-membered heterocyclyl; wherein bonds a1, a2, a3 and a4 are either a single or a double bond; wherein any of Ring A1, A2, A3 or A4 may be optionally fused to a phenyl ring or a 5- or 6-membered heteroaryl ring;b) Ring A has a structure according to Ring A5:wherein Ring A5 is selected from a monocyclic (7C)cycloalkyl, a monocyclic 7- membered heterocyclyl, or a bridged, fused, or spirocyclic (7-10C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 7- to 10- membered heterocyclyl; c) Ring A is a spirocylic ring according to Ring A6 shown below,:wherein Ring A6a is a (3-6C)cycloalkyl or 4- to 7-membered heterocylic ring, wherein Ring A6a is spiro-fused to Ring A6b, and Ring A6b is a 4-7membered heterocyclic ring; wherein any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available carbon atom by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1, OC(O)RA1, C(O)N(RA1)RA2, N(RA1)C(O)RA2; wherein RA1and RA2are each independently selected from hydrogen or (1-4C)alkyl; and Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available nitrogen atom by (1-4C)alkyl; and any (1-6C)alkyl in a substituent on Ring A is optionally further substituted by one or more of halo, cyano, (1-4C)alkoxy, hydroxy or NH2;and any phenyl or heteroaryl ring fused to Ring A1, A2, A3 or A4 may be optionally substituted by one or more substituents selected from from (1-6C)alkyl, halo, (1-6C)- haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-4C)alkyl; and wherein if Ring A is selected from Ring A1, A5 or A6, then the atom to which Ring A is attached to in Ring B is a carbon atom. (62) One of the following applies: a) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Ring A1, A2, A3 or A4 are selected from saturated or partially saturated monocyclic, bridged, fused, or spirocyclic (5-8C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 5- to 8-membered heterocyclyl; wherein bonds a1, a2, a3 and a4 are either a single or a double bond; wherein any of Ring A1, A2, A3 or A4 may be optionally fused to a phenyl ring or a 6-membered heteroaryl ring; b) Ring A has a structure according to Ring A5:wherein Ring A5 is selected from a monocyclic (7C)cycloalkyl or a monocyclic 7-membered heterocyclyl; or c) Ring A is a spirocylic ring according to Ring A6 shown below,:Ring A6 wherein in Ring A6, Ring A6a is a (3-6C)cycloalkyl or 4- to 6-membered heterocylic ring, and Ring A6b is a 4-7 membered heterocyclic ring, wherein Ring A6a is spiro-fused to Ring A6b; wherein any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available carbon atom by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-3C)alkyl; wherein any (1-3C)alkyl is optionally further substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available nitrogen atom by (1-2C)alkyl; and any phenyl or heteroaryl ring fused to Ring A1, A2, A3 or A4 may be optionally substituted by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-3C)alkyl; and wherein if Ring A is selected from Ring A1, A5 or A6, then the atom to which Ring A is attached to in Ring B is a carbon atom. (63) One of the following applies: a) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Ring A1, A2, A3 or A4 are selected from saturated or partially saturated monocyclic, bridged, fused, or spirocyclic (5-8C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 5- to 8-membered heterocyclyl; wherein bonds a2, a3 and a4 are either a single or a double bond; wherein any of Ring A1, A2, A3 or A4 may be optionally fused to a phenyl ring; b) Ring A has a structure according to Ring A5:wherein Ring A5 is selected from a monocyclic (7C)cycloalkyl, a monocyclic 7- membered heterocyclyl, or a c) Ring A is a spirocylic ring according to Ring A6 shown below,:Ring A6wherein Ring A6a is a (3-4C)cycloalkyl, and Ring A6b is a 5- or 6-membered heterocyclic ring, wherein Ring A6a is spiro-fused to Ring A6b; wherein any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available carbon atom by one or more substituents independently selected from fluoro, chloro, hydroxy, oxo, (1-2C)alkyl, (1-2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, methoxy or hydroxy; and any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available nitrogen atom by methyl; and any phenyl ring fused to one of Ring A1, A2, A3 and A4 may be optionally substituted by one or more substituents selected from methyl, fluoro, cyano, NRA3RA4or ORA3, wherein RA3and RA4are each independently selected from hydrogen or methyl; and wherein if Ring A is selected from Ring A1, A5 or A6, then the atom to which Ring A is attached to in Ring B is a carbon atom. (64) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Rings A1, A2, A3 or A4 are as defined in any one of paragraphs (61) to (63). (65) Ring A is selected from a ring with a structure according to Ring A1 below:wherein Rings A1, A2, A3 or A4 are as defined in any one of paragraphs (61) to (63). (66) Ring A has a structure according to Ring A5:wherein Ring A5 is as defined in any one of paragraphs (61) to (63). (67) Ring A is is a spirocylic ring according to Ring A6 shown below,:wherein Ring A6 is as defined in any one of paragraphs (61) to (63).

[0078] Suitably, Ring A is as defined in any one of paragraphs (1) to (7) above. More suitably, Ring A is as defined in any one of paragraphs (3) to (7) above. Most suitably, Ring A is as defined in paragraph (6) or (7) above.

[0079] Suitably, in certain embodiments, Ring A is as defined in any one of paragraphs (58) to (67) above. More suitably, Ring A is as defined in any one of paragraphs (63) to (67) above. Most suitably, Ring A is as defined in paragraph (64) or (65) above.

[0080] Suitably, Ring A is as defined in any one of paragraphs (1) to (23), or (58) to (67) above. More suitably, Ring A is as defined in any one of paragraphs (3a) to (7) above. Most suitably, Ring A is as defined in paragraph (5a), (6) or (7) above.

[0081] Suitably, Ring B is as defined in any one of paragraphs (8) to (23) above. Suitably, Ring B is as defined in any one of paragraphs (13) to (23) above. More suitably, Ring B is as defined in any one of paragraphs (19) to (23) above. Most suitably, Ring B is as defined in paragraph (22) or (23) above.

[0082] Suitably, if a nitrogen atom in Ring A is attached to Ring B, then the atom in Ring B to which the nitrogen is attached must be a carbon atom, for example:.

[0083] Suitably, if a nitrogen atom in Ring B is attached to Ring A, then the atom in Ring A to which the nitrogen is attached must be a carbon atom, for example:.

[0084] Suitably, B1or Y1must be carbon if Ring A is selected from one of the rings in list (a) in paragraph (3) (or (3a)), such as:,wherein the above rings may be substituted as defined herein. Thus, when Ring A is selected from one of the rings in list a), the atom in Ring B which is attached to the linking nitrogen atom in Ring A must be a carbon atom.

[0085] Suitably, if B1or Y1are nitrogen, then the atom in Ring A which is attached to B1or Y1in Ring B must be a carbon atom. More suitably, if B1or Y1are nitrogen, then Ring A is selected from one of the rings in list b) in paragraph (3) (or (3a)), such as: b) Ring A is selected from: ,wherein the above rings may be substituted as defined herein.

[0086] Suitably, RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare as defined in any one of paragraphs (14) to (26) above. More suitably, RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare as defined in any one of paragraphs (24) to (26) above. Most suitably, RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare as defined in paragraph (25) or (26) above.

[0087] Suitably, RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare as defined in any one of paragraphs (14) to (26a) above. More suitably, RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare as defined in any one of paragraphs (24a), (25a) and (26a) above. Most suitably, RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare as defined in paragraph (25a) or (26a) above.

[0088] Suitably, RD4is as defined in any one of paragraphs (27) to (29a) above. More suitably, RD4is as defined in paragraph (28) or (29) above. Most suitably, RD4is as defined in paragraph (29) above.

[0089] Suitably, RZ4is as defined in any one of paragraphs (27) to (29a) above. More suitably, RZ4is as defined in paragraph (28) or (29) above. Most suitably, R4is as defined in paragraph (29) above.

[0090] Suitably, RD7is as defined in paragraph (30) or (30a) above.

[0091] Suitably, RY7is as defined in paragraph (31) above.

[0092] Suitably, RZ7and RZ8are as defined in paragraph (31a) or (31b) above. More suitably, RZ7and RZ8are as defined in paragraph (31b) above.

[0093] Suitably, RZ7and RZ8are as defined in paragraph (31c) or (31d) above. More suitably, RZ7and RZ8are as defined in paragraph (31d) above.

[0094] Suitably, RBis as defined in any one of paragraphs (32) to (36) above. More suitably, RBis as defined in any one of paragraphs (34) to (36) above. Most suitably, RBis as defined in paragraph (35), (35a) or (36) above.

[0095] Suitably, R1aand R1bare as defined in any one of paragraphs (37) to (40) above. More suitably, R1aand R1bare as defined in any one of paragraphs (38) to (40) above. Most suitably, R1aand R1bare as defined in paragraph (39) or (40) above.

[0096] Suitably, R3aand R3bare as defined in any one of paragraphs (41) to (43) above. More suitably, R3aand R3bare as defined in paragraph (42) or (43) above. Most suitably, R3aand R3bare as defined in paragraph (43) above.

[0097] Suitably, R4aand R4bare as defined in any one of paragraphs (44) to (46) above. More suitably, R4aand R4bare as defined in paragraph (45) or (46) above. Most suitably, R4aand R4bare as defined in paragraph (46) above.

[0098] Suitably, R5is as defined in paragraph (47) or (48) above. Most suitably, R5is as defined in paragraph (48) above.

[0099] Suitably, R6is as defined in any one of paragraphs (49) to (51a) above. More suitably, R6is as defined in paragraph (50), (51) or (51a) above. Most suitably, R6is as defined in paragraph (51) or (51a) above.

[0100] Suitably, R7is as defined in any one of paragraphs (52), (53) or (54) above. More suitably, R7is as defined in paragraph (54) above.

[0101] Suitably, R8is as defined in any one of paragraphs (55) to (57) or (57a) above. More suitably, R8is as defined in paragraph (56), (57) or (57a) above. Most suitably, R8is as defined in paragraph (57) or (57a) above.

[0102] In an embodiment: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B4is selected from S, O, N, NRB4Nor CRB4; B5is selected from N or CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; C2is selected from N or CRC2; C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; C6is selected from N or CRC6; with the proviso that no more than one of C2, C3, C4, C5or C6is nitrogen; D2is selected from N or CRD2; D3is selected from N; D4is selected from N or CRD4; D5is selected from N or C; D6is selected from S, O, N, NRD6Nor CRD6; D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; RN3is selected from hydrogen or (1-2C)alkyl; with the proviso that the 9-membered bicyclic ring comprising D2, N, D4, D5, N,D7, D8and D9comprises no more than 4 heteroatoms in the ring structure; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O) D5, D6, D7, D8and D9are a heteroatom; Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3;Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, Y6,Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; Z2is selected from N or CRZ2; Z3is selected from N or CRZ3; Z4is selected from N or CRZ4; Z5is selected from N or C; Z6is selected from N or CRZ6; Z7is selected from N or CRZ7; Z8is selected from N or CRZ8; Z9is selected from N or CRZ9; Z10is selected from N or C; RN7is selected from hydrogen or (1-2C)alkyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, N(RN7), C(O), Z8, Z9and Z10are a heteroatom; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8and RZ9independently as defined herein.

[0103] In an embodiment: B1is selected from N or C; B2is CRB2; B4is selected from S, NRB4Nor CRB4; B5is CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; C2is selected from N or CRC2; C4is CRC4;C5is selected from N or CRC5; C6is CRC6; with the proviso that no more than one of C2, C4, C5or C6is nitrogen; D2is CRD2; D3is N; D4is CRD4; D5is selected from C; D6is selected from S, O or N; D7is selected from N, CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; RN3is selected from hydrogen or methyl; with the proviso that the 9-membered bicyclic ring comprising D2, N, D4, D5, N, D7, D8and D9comprises no more than 4 heteroatoms in the ring structure; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O) D5, D6, D7, D8and D9are a heteroatom; Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, N, Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; Z2is CRZ2; Z3is CRZ3; Z4is CRZ4; Z5is C; Z6is CRZ6; Z7is CRZ7; Z8is CRZ8; Z9is CRZ9;Z10is C; RN7is selected from hydrogen or methyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6,Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, N(RN7), C(O), Z8, Z9and Z10are a heteroatom; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8and RZ9are independently as defined herein.

[0104] In an embodiment: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RZ2, RZ3, RZ6and RZ9RY8are independently selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy; RC6is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy, (4-6C)cycloalkyl or a 5- to 6 membered heterocyclyl; RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare selected from hydrogen or methyl; RD4, RD7, RY7, RZ4, RZ7and RZ8are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.

[0105] In an embodiment: RB2, RB3, RB4, RB5RC2, RC3, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen or halo, preferably hydrogen; RC4and RC5are independently selected from hydrogen, halo or methoxy, preferably hydrogen or methoxy; RC6is selected from hydrogen, halo or a 6 membered monocyclic heterocyclyl; RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare independently selected from hydrogen or methyl; RD4is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; each of RZ2, RZ3, and RZ9are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3);RZ4is selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; RZ6is selected from hydrogen, halo or hydroxy, methyl, methoxy or fluoromethyl (e.g. CF3); one of RZ7and RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3, and the other is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.

[0106] In an embodiment: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RZ2, RZ3, RZ6and RZ9are hydrogen; RD2is selected from hydrogen or halo, e.g. fluoro, chloro or bromo; RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare independently selected from hydrogen or methyl; RD4and RZ4are selected from hydrogen, fluoro, bromo, iodo, cyano or methyl; RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein; and one of RZ7and RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3, and the other is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.

[0107] In certain embodiments, the nitrogen which links Ring A to Ring B is optionally in the form of an N-oxide, e.g..

[0108] In a particular embodiment, one or more of the nitrogen atoms which make up Ring B may be in the form of an N-oxide. In a further embodiment, any nitrogen in the “D3” position in Ring B is optionally in the form of an N-oxide, for example:wherein D2to D9are as defined herein.

[0109] By way of further example, the nitrogen in the “D3” position may be in the form of an N-oxide as shown below::wherein RD2, RD4and RD7are as defined herein.

[0110] In an embodiment, the compound is of Formula (Ia) (a sub-formula of formula (I) defined herein) below:wherein Ring A, Ring B, R1a, R1b, R6and R8are as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0111] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (37) to (40) above;R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7) above; and Ring B is as defined in any one of paragraphs (8) to (23) above.

[0112] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0113] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (37) to (40) above; R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7) or (58) to (67) above; and Ring B is as defined in any one of paragraphs (8) to (23) above.

[0114] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (58) to (67) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0115] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (63) to (67) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0116] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (3a) to (7) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0117] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (50) or (51) above;R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0118] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in paragraph (64) or (65) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0119] In an embodiment of Formula (Ia): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0120] In an embodiment of Formula (Ia): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0121] In an embodiment of Formula (Ia): R1aand R1bare as defined in paragraph (39) or (40) above; R6is fluoro; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0122] In an embodiment of Formula (Ia): R1aand R1bare as defined in paragraph (39) or (40) above; R6is chloro; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0123] In an embodiment of Formula (Ia): R1aand R1bare as defined in paragraph (39) or (40) above; R6is trifluoromethyl;R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0124] In an embodiment, the compound is of Formula (Ib) or (Ic) (sub-formulae of formula (I) defined herein) below:wherein Ring A, Ring B, R6and R8are as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0125] In an embodiment of Formula (Ib) and (Ic): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7) above; and Ring B is as defined in any one of paragraphs (8) to (23) above.

[0126] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0127] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (50) or (51) above;R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (58) to (67) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0128] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0129] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (63) to (67) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0130] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in paragraphs (64) or (65) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0131] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (13) to (23) above.

[0132] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0133] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (51a) above; R8is as defined in paragraph (57a) above; Ring A is as defined in any one of paragraphs (3) to (7) above; and Ring B is as defined in any one of paragraphs (19) to (23) above.

[0134] In an embodiment of Formula (Ib) and (Ic): R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; andRing B is as defined in paragraph (22) or (23) above.

[0135] In an embodiment of Formula (Ib) and (Ic): R6is fluoro; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0136] In an embodiment of Formula (Ib) and (Ic): R6is chloro; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0137] In an embodiment of Formula (Ib) and (Ic): R6trifluoromethyl; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in paragraph (5a,) (6) or (7) above; and Ring B is as defined in paragraph (22) or (23) above.

[0138] In an embodiment, the compound is of Formula (IIa) (a sub-formula of formula (I) defined herein) below:wherein Ring A, Ring B, R1a, R1b, RD2, RD4and RD7are as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0139] In an embodiment of Formula (IIa): R1aand R1bare as defined in any one of paragraphs (37) to (40) above; R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7) above; RD2is as defined in any one of paragraphs (14) to (26) above;RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.

[0140] In an embodiment of Formula (IIa): R1aand R1bare as defined in any one of paragraphs (37) to (40) above; R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0141] In an embodiment of Formula (IIa): R1aand R1bare as defined in any one of paragraphs (37) to (40) above; R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7), or (58) to (67) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0142] In an embodiment of Formula (IIa): R1aand R1bare as defined in any one of paragraphs (37) to (40) above; R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (58) to (67) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0143] In an embodiment of Formula (IIa): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (63) to (67) above; RD2is as defined in any one of paragraphs (24) to (26) and (26a) above RD4is as defined in paragraph (28) or (29) above;RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (34) to (36) above.

[0144] In an embodiment of Formula (IIa): R1aand R1bare as defined in any one of paragraphs (38) to (40) above; R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (3) to (7) above; RD2is as defined in any one of paragraphs (24) to (26) and (26a) above RD4is as defined in paragraph (28) or (29) above; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (34) to (36) above.

[0145] In an embodiment of Formula (IIa): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (64) or (65) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35) above.

[0146]

[0147] In an embodiment of Formula (IIa): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35) above.

[0148] In an embodiment of Formula (IIa): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (64) or (65) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; andRD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35a) above.

[0149] In an embodiment of Formula (IIa): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35a) above.

[0150] In an embodiment of Formula (IIa): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (6) or (7) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0151] In an embodiment of Formula (IIa): R1aand R1bare as defined in paragraph (39) or (40) above; R6is as defined in paragraph (51a) above; R8is as defined in paragraph (57a) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0152] In an embodiment, the compound is of Formula (IIb) or (IIc) (sub-formulae of formula (I) defined herein) below:wherein Ring A, Ring B, R6, R8, RD2, RD4and RD7are as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0153] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7), or (58) to (67) above(1) to (7); RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined anywhere herein.

[0154] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0155] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (1) to (7), or (58) to (67) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0156] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (58) to (67) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0157] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in any one of paragraphs (63) to (67) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0158] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in paragraph (64) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0159] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in paragraph (65) above;RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0160] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in paragraph (66) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0161] In an embodiment of Formula (IIb) and (IIc): R6is as defined in any one of paragraphs (49) to (51) above; R8is as defined in any one of paragraphs (55) to (57) above; Ring A is as defined in paragraph (67) above; RD2is as defined in any one of paragraphs (14) to (26) above; RD4is as defined in any one of paragraphs (27) to (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (32) to (36) above.

[0162] In an embodiment of Formula (IIb) and (IIc): R6is as defined in paragraph (50) or (51) above; R8is as defined in paragraph (56) or (57) above; Ring A is as defined in any one of paragraphs (3) to (7) above; RD2is as defined in any one of paragraphs (24) to (26) above RD4is as defined in paragraph (28) or (29) above; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (34) to (36) above.

[0163] In an embodiment of Formula (IIb) and (IIc): R6is as defined in paragraph (51) or (51a) above; R8is as defined in paragraph (57) or (57a) above; Ring A is as defined in any one of paragraphs (3a) to (7) above; RD2is as defined in any one of paragraphs (24) to (26) above RD4is as defined in paragraph (28) or (29) above;RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of paragraphs (34) to (36) above.

[0164] In an embodiment of Formula (IIb) and (IIc): R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35) above.

[0165] In an embodiment of Formula (IIb) and (IIc): R6is as defined in paragraph (51) above; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0166] In an embodiment of Formula (IIb) and (IIc): R6is fluoro; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0167] In an embodiment of Formula (IIb) and (IIc): R6is as defined in paragraph (51a) above; R8is as defined in paragraph (57a) above; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (25) or (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35a) above.

[0168] In an embodiment of Formula (IIb) and (IIc):R6is chloro; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (6) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0169] In an embodiment of Formula (IIb) and (IIc): R6is trifluoromethyl; R8is as defined in paragraph (57) above; Ring A is as defined in paragraph (6) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0170] In an embodiment of Formula (IIb) and (IIc): R6is chloro or trifluoromethyl; R8is chloro; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) or (29a) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0171] In an embodiment of Formula (IIb) and (IIc): R6is chloro or trifluoromethyl; R8is chloro; Ring A is as defined in paragraph (5a) or (7) above; RD2is as defined in paragraph (26) above; RD4is as defined in paragraph (29) or (29a) above; and RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (35a) above.

[0172] In an embodiment of Formula (IIb) and (IIc): R6is chloro or trifluoromethyl; R8is chloro; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is hydrogen; RD4is hydrogen; andRD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph (36) above.

[0173] In an embodiment of Formula (IIb) and (IIc): R6is chloro or trifluoromethyl; R8is chloro; Ring A is as defined in paragraph (5a), (6) or (7) above; RD2is hydrogen; RD4is hydrogen; and RD7is NH2.

[0174] Suitably, the compound is not: 4-(6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-[4-(4- methylpiperidin-1-yl)phenyl]pyrrolidine-2-one; or [1-(5,6-dimethylthieno[3,2-e]pyrimidin-4-yl)piperidin-4-yl]-(7-fluoro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl)methanone.

[0175] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic or bicylclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0176] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0177] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered monocyclic heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S or a 5- to 10-membered biccyclic heterocyclyl ring (e.g. fused, bridged or spirocyclic) comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5- or 6- membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one)].

[0178] Suitably, an aryl group is phenyl.

[0179] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following: (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(3-(pyridin-3-yl)piperidin-1- yl)methanone;(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)piperazin-2- yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)(6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)piperidin-3-yl)(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)pyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (3-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-azabicyclo[3.1.0]hexan-1-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)thiomorpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-methylmorpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone;((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6-chloro-8-fluoro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-8-fluoro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-6-fluoro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,4R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (methylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((3R,6S)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1-methylpiperazin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-((cyclopropylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- hydroxyethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methoxypyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((5R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4RS)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4SR)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,5-difluoropiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-(cyclopropylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (ethylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-((cyclobutylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(piperidin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(R)-(4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(6,8-dichloro-1,1-dimethyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)morpholin-2- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3-yl)morpholin-2- yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-6,6-dimethyl-4-(pyridin-3- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyrimidin-5- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(imidazo[1,2-a]pyrazin-5- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-methyloxazolo[4,5- c]pyridin-7-yl)morpholin-2-yl)methanone; rac-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3- yl)thiomorpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-4-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone;((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-7-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-6-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(isothiazol-4- yl)morpholin-2-yl)methanone; ((R)-4-([1,2,4]triazolo[4,3-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-1-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3S)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(1-(pyridin-3-yl)pyrrolidin-3- yl)methanone; ((2RS,4SR)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(6-aminoimidazo[1,2-a]pyrazin-3-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2RS,4RS)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-2-oxabicyclo[2.1.1]hexan-1-yl)(6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-amino-4,6-dibromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-methyloxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; N-(7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)acetamide; ((R)-4-(2-amino-4,6-dichlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-chlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-amino-7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridine-4-carbonitrile; ((R)-4-(2-amino-4-iodooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((R)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2R,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)morpholine 4-oxide; 2-amino-7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridine 5-oxide; ((2R,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)morpholin-3-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((3- morpholinopropyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-amino-4-methoxyoxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-amino-7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-4(5H)-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(3-fluoroazetidin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(3,3- difluoroazetidin-1-yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(3- methoxyazetidin-1-yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((2R,6R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 5-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)morpholino)- 2,7-naphthyridin-1(2H)-one; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-fluoropiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6,6-dimethylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((R)- 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methoxypiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(thiazolo[4,5-c]pyridin-7- yl)morpholin-2-yl)methanone;(1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-hydroxypiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[5,4-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-ethylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-7-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-oxa-7-azaspiro[2.5]octan-5-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(piperazin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (methylthio)thiazolo[5,4-c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-(aminomethyl)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminobenzo[d]oxazol-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyrazolo[1,5- c]pyrimidin-3-yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylpiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(3,4- dimethoxyphenyl)morpholin-2-yl)methanone;((2R,6R)-4-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-azabicyclo[2.2.2]octan-4-yl)(6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-fluoro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-8-fluoro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-methoxybenzo[d]oxazol-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(5-methoxypyridin-3- yl)morpholin-2-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(hydroxymethyl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(1,7-naphthyridin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2,7-naphthyridin-4-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminothiazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)-2-oxa-5- azabicyclo[2.2.1]heptan-1-yl)((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)- yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(hydroxymethyl)morpholin-2-yl)((S)-8- chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(methoxymethyl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(methoxymethyl)morpholin-2-yl)((S)-8- chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(3-amino-1,7-naphthyridin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminothiazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-azabicyclo[2.2.1]heptan-4-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-1,7-naphthyridin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (2S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)morpholine-2-carboxylic acid; (2S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)-N,N-dimethylmorpholine-2-carboxamide; (2S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)-N-methylmorpholine-2-carboxamide; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((2R)-4-(4-(morpholin-2- yl)pyridin-3-yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,6-dihydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,6-dihydro-2H-pyran-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-8- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6-chloro-1-methyl-8- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxypiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-amino-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)piperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2RS,4SR,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2- yl)((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R*,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((2R,4S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 5-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)imidazo[1,2-a]pyrazine-2-carboxamide; 4-(2-((7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)amino)ethyl)piperazin-2-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- morpholinoethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(4,4- difluoropiperidin-1-yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- thiomorpholinoethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(1,1- dioxidothiomorpholino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone;2-((7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)amino)-1-(piperazin-1-yl)ethan-1-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(imidazo[1,2-a]pyrazin-3- yl)morpholin-2-yl)methanone; ((R)-4-(2-amino-1H-imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(1H-imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-methyl-1H- imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(1-methyl-1H- imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; or ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(oxazolo[4,5-c]pyridin-7- yl)morpholin-2-yl)methanone.

[0180] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following: (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(3-(pyridin-3-yl)piperidin-1- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)piperazin-2- yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)(6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)piperidin-3-yl)(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)pyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (3-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-azabicyclo[3.1.0]hexan-1-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)thiomorpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-methylmorpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6-chloro-8-fluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-8-fluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-6-fluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,4R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (methylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((3R,6S)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1-methylpiperazin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-((cyclopropylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- hydroxyethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methoxypyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((5R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4RS)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4SR)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,5-difluoropiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-(cyclopropylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-(ethylamino)oxazolo[4,5- c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-((cyclobutylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(piperidin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(6,8-dichloro-1,1-dimethyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)morpholin-2- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3-yl)morpholin-2- yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-6,6-dimethyl-4-(pyridin-3- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyrimidin-5-yl)morpholin-2- yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(imidazo[1,2-a]pyrazin-5- yl)morpholin-2-yl)methanone ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-methyloxazolo[4,5- c]pyridin-7-yl)morpholin-2-yl)methanone;rac-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3- yl)thiomorpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-4-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-7-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-6-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(isothiazol-4-yl)morpholin-2- yl)methanone; ((R)-4-([1,2,4]triazolo[4,3-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-1-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;((1R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(1-(pyridin-3-yl)pyrrolidin-3- yl)methanone; ((1R,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3S)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((2S*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(6-aminoimidazo[1,2-a]pyrazin-3-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2RS,4RS)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-2-oxabicyclo[2.1.1]hexan-1-yl)(6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4,6-dibromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-methyloxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; N-(7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)acetamide; ((R)-4-(2-amino-4,6-dichlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-chlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; or ((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.Intermediates

[0181] In another aspect, the present invention provides novel intermediates as defined herein, in particular: (S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline (referred to herein as (INT-A)); (S)-8-chloro-1-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (referred to herein as INT-B)); or 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinoline (referred to herein as (X-B)); or a salt or solvate thereof.

[0182] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound of the Formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.

[0183] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0184] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as amixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0185] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess activity against METTL1.

[0186] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H(D), and3H (T); C may be in any isotopic form, including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like.

[0187] It is also to be understood that certain compounds of the Formula (I) (and compounds of subformulas thereof) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess activity against METTL1.

[0188] It is also to be understood that certain compounds of the Formula (I) (and compounds of subformulas thereof) may exhibit polymorphism, and that the invention encompasses all such forms that possess activity against METTL1.

[0189] Compounds of the Formula (I) (and compounds of subformulas thereof) may exist in a number of different tautomeric forms and references to compounds of the Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate- forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0190] Compounds of the Formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0191] In a particular embodiment, the nitrogen which links Ring A to Ring B may be in the form of an N-oxide, e.g..

[0192] In a particular embodiment, one or more of the nitrogen atoms which make up Ring B may be in the form of an N-oxide. In a further embodiment, any nitrogen in the “D3” position in Ring B is optionally in the form of an N-oxide, e.g.:.

[0193] The compounds of Formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I) and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I).

[0194] Accordingly, the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.

[0195] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0196] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0197] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula(I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl, ethyl and tert-butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

[0198] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- 10alkoxycarbonyl groups such as ethoxycarbonyl, N,N –(C1-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0199] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-4alkoxy- C2-4alkylamine such as 2-methoxyethylamine, a phenyl-C1-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0200] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl.

[0201] The in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro- drug).

[0202] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0203] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein. Synthesis

[0204] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0205] The intermediate compounds described in the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. Synthesis of (INT-A)

[0206] In a particular embodiment there is provided a method for the synthesis of an intermediate of the formula (INT-A):(INT-A) the method comprising, reacting a compound of Formula (X-A)(X-A) with a compound according to formula (Y-A):(Y-A) under appropriate reaction conditions.

[0207] Suitably, compound (X-A) and (Y-A) are reacted in an appropriate solvent. Suitably, the solvent is an alcohol, for example ethanol, methanol, isopropanol or n-butanol. Most suitably, the solvent is isopropanol.

[0208] Suitably, compound (X-A) and (Y-A) are reacted at a temperature of from 60°C to 100°C, more suitably from 70°C to 90°C.

[0209] Suitably, the method optionally includes isolating intermediate (INT-A) as a suitable salt, for example a N-acetyl-L-phenylalanine salt.

[0210] Suitably, a compound of formula (X-A) may be prepared using appropriate techniques known in the art using commercially available intermediates as building blocks. A particular example of the preparation of the compound of Formula X-A is provided in Scheme A1 below:Scheme A1 – example synthesis of compound (X-A)

[0211] A particular example of the preparation of the intermediate of Formula INT-A isprovided in Scheme A2 below:Scheme A2 – example synthesis of compound (INT-A) Synthesis of (INT-B)

[0212] In a particular embodiment there is provided a process for the synthesis of an intermediate of the formula (INT-B) by step (c-1) shown below, the process comprising: (c-1) reacting a compound of Formula (X-B)(X-B) with a compound according to formula (Y-A):(Y-B) to form an intermediate of the formula (INT-B):(INT-B).

[0213] Suitably, compound (X-B) and (Y-B) are reacted in an appropriate solvent. Suitably, the solvent is an alcohol, for example ethanol methanol, isopropanol or n-butanol. Most suitably, the solvent is methanol.

[0214] Suitably, compound (X-B) and (Y-B) are reacted under stereoselective hydrogenation conditions.

[0215] Suitably, compound (X-A) and (Y-A) are reacted at a temperature of from 10°C to 40°C, more suitably from 15°C to 30°C. Suitably, compound (X-A) and (Y-A) are reacted at a ambient temperatures, e.g.20°C to 25°C

[0216] Suitably, compound (X-B) and (Y-B) are reacted the presence of a chiral catalyst, for example [Rh(η5-C5Me5)Cl2]2.

[0217] Suitably, compound (X-B) and (Y-B) are reacted in the presence of a Lewis base, for example DABCO (1,4-Diazabicyclo[2.2.2]octane).

[0218] Suitably, the compound (X-B) and (Y-B) are reacted in the presence of a hydrogen source, such as an alcohol or formic acid.

[0219] Suitably, compound (X-B) and (Y-B) are reacted the presence of [Rh(η5- C5Me5)Cl2]2, DABCO and formic acid.

[0220] Suitably, the intermediate (INT-B) is isolated as a suitable salt, for example a hydrochloric acid salt.

[0221] In a particular embodiment, the process further comprises forming a compound intermediate (W-B) by step (a-1) shown below: (a-1) reacting a compound (V-B) shown below:with a compound having the structural formula:to form a compound of the formula (W-B):.

[0222] Suitably, a compound of formula (V-B) may be prepared using appropriate techniques known in the art using commercially available intermediates as building blocks.

[0223] Suitably the compound according to (V-B) is reacted with a compound having the structural formula:.

[0224] Suitably, the reaction according to step (a-1) is performed in the presence of a palladium catalyst, for example Pd(dppf)Cl2([1,1′ Bis(diphenylphosphino)ferrocene]dichloropalladium(II)).

[0225] Suitably, the reaction according to step (a-1) is performed in the presence of a base, e.g. potassium carbonate.

[0226] Suitably, the compound according to formula (W-B) is purified, e.g. to to separate it from the catalyst.

[0227] In a particular embodiment, the process further comprises forming an intermediate compound (X-B) by step (b-1) shown below: (b-1) reacting a compound (W-B) shown below:with MeMgBr; to form a compound of the formula (X-B):

[0228] Suitably, step (b-1) is performed in a suitable solvent, such as toluene.

[0229] Suitably, step (b-1) is performed at a temperature of from 0 to 30 °C.

[0230] A particular example of the preparation of the compound of Formula X-B is provided in Scheme B1 below:Scheme B1 – example synthesis of compound (X-B)

[0231] A particular example of the preparation of the intermediate of Formula INT-B is provided in Scheme B2 below:Scheme B2 – example synthesis of compound (INT-B)

[0232] A particular example of the conversion of intermediate Formula INT-B into a hydrochloric acid salt is provided in Scheme B3 below:Scheme B3 – preparation of hydrochloric acid salt of (INT-B)

[0233] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0234] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0235] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0236] For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0237] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0238] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with asuitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0239] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0240] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0241] Resins may also be used as a protecting group.

[0242] The methodology employed to synthesise a compound of Formula (I) will vary depending on the nature of the variable groups. Suitable processes for their preparation are described further in the accompanying Examples.

[0243] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0244] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art. Biological Activity

[0245] The METTL1 enzyme and cell assays described in accompanying Example section may be used to measure the pharmacological effects of the compounds of the present invention.

[0246] Although the pharmacological properties of the compounds of Formula (I) vary with structural change, as expected, the compounds of the invention were found to be active in these METTL1 assays.

[0247] In general, the compounds of the invention demonstrate an IC50of 100 µM or less in the METTL1 enzyme assay (METTL1 + WDR4 methyltransferase assay) described herein, with particularly preferred compounds of the invention demonstrating an IC50of 1 µM or less and the most preferred compounds of the invention demonstrating an IC50of 0.1 µM or less.

[0248] In the METTL1 cell assay (“METTL1 InCellPulse Assay”) described in the Example section, the compounds of Formula (I) may suitably possess an IC50of less than 45 µM, with particularly preferred compounds of the invention demonstrating an IC50of 1 µM or less and the most preferred compounds demonstrating an activity of 0.12 µM or less.

[0249] In the MSD m7G modification assay described in the Example section, the compounds of Formula (I) may suitably possess an IC50of less than 10 µM, with particularly preferred compounds of the invention demonstrating an IC50of 1 µM or less and the most preferred compounds demonstrating an activity of 0.2 µM or less.

[0250] In the CTG proliferation assay described in the Example section, the compounds of Formula (I) may suitably possess an IC50of less than 10 µM, with particularly preferred compounds of the invention demonstrating an IC50of 5 µM or less and the most preferred compounds demonstrating an activity of 2 µM or less. Pharmaceutical Compositions

[0251] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0252] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions,dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0253] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0254] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a condition and / or disease (such as a proliferative condition) referred to herein, slow its progression and / or reduce the symptoms associated with the condition and / or disease. The condition or disease (e.g. a proliferative condition) may be selected from any of those described herein.

[0255] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 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.

[0256] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0257] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.Therapeutic Uses and Applications

[0258] The present invention provides compounds that function as inhibitors of METTL1 activity.

[0259] The present invention therefore provides a method of inhibiting METTL1 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0260] The present invention also provides a method of treating a disease or disorder in which METTL1 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0261] Suitably, the disease or disorder in which METTL1 activity is implicated is cancer.

[0262] Suitably, the cancer is selected from solid organ cancer, lung cancer (e.g. non- small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T- ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervicalcancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma.

[0263] Suitably, the cancer may be a haematologic cancer, such as: ● acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; ● chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; ● Acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); ● Chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia; or ● Lymphoma including non-Hodgkin lymphoma (NHL), e.g. Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL); or primary effusion lymphoma (PEL).

[0264] Suitably, the cancer may be a solid organ cancer, such as: ● Glioma including low grade glioma and glioblastoma multiforme / astrocytoma; ● Sarcoma including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma; ● Pancreatic cancer including pancreatic ductal adenocarcinoma; ● Bladder carcinoma including urothelial (transitional cell) bladder cancer; ● Hepatocellular carcinoma including adult and paediatric hepatocellular carcinoma and hepatoblastoma; ● Intrahepatic cholangiocarcinoma; ● Gastric cancer including gastric adenocarcinoma; ● Non-small cell lung cancer (NSCLC) including lung adenocarcinoma and lung squamous cell carcinoma; ● Prostate carcinoma including prostate adenocarcinoma; ● Oesophageal squamous cell carcinoma; ● Head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue, nasopharyngeal carcinoma; ● Neuroblastoma; ● Colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma; and● Cervical cancer including cervical squamous cell carcinoma and cervical adenocarcinoma; ● Adrenocortical carcinoma; ● Breast cancer including breast invasive carcinoma; ● Mesothelioma ● Ovarian cancer including epithelial ovarian carcinoma; or ● Renal cell carcinoma (RCC) including clear cell renal cell carcinoma (ccRCC).

[0265] The present invention also provides a method of inhibiting metastasis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0266] The present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0267] The present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0268] The present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Suitably, the cancer is selected from solid organ cancer, lung cancer (e.g. non- small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T- ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamouscell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma.

[0269] The present invention provides a method of treating a haematologic cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. The haematologic cancer may be selected from acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia and acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia; or lymphoma including non-Hodgkin lymphoma (NHL), e.g. Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL); or primary effusion lymphoma (PEL).

[0270] The present invention provides a method of treating a solid organ cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. The solid organ cancer may be selected from glioma including low grade glioma and glioblastoma multiforme / astrocytoma; sarcoma including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma; pancreatic cancer including pancreatic ductal adenocarcinoma; bladder carcinoma including urothelial (transitional cell) bladder cancer; hepatocellular carcinoma including adult and paediatric hepatocellular carcinoma and hepatoblastoma; intrahepatic cholangiocarcinoma; gastric cancer including gastric adenocarcinoma; non-small cell lung cancer (NSCLC) including lung adenocarcinoma and lung squamous cell carcinoma; prostate carcinoma including prostate adenocarcinoma; oesophageal squamous cell carcinoma; head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma; neuroblastoma; colorectal cancer including colonadenocarcinoma and rectal adenocarcinoma; cervical cancer including cervical squamous cell carcinoma and cervical adenocarcinoma; adrenocortical carcinoma; breast cancer including breast invasive carcinoma; mesothelioma; ovarian cancer including epithelial ovarian carcinoma; or renal cell carcinoma (RCC) including clear cell renal cell carcinoma (ccRCC).

[0271] The present invention provides a method of treating leukaemia, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0272] The present invention provides a method of treating AML leukaemia, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0273] The present invention provides a method of treating hepatocellular carcinoma, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0274] The present invention provides a method of treating non-cancerous tumour growth, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0275] The present invention provides a method of treating ameloblastoma, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0276] Suitably, the disease or disorder in which METTL1 activity is implicated is cancer.

[0277] The present invention provides a method of treating cardiac fibrosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0278] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0279] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment ofcardiac fibrosis.

[0280] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[0281] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of non- cancerous tumour growth. In a particular embodiment, the non-cancerous tumour growth is ameloblastoma.

[0282] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. Suitably, the cancer is selected from solid organ cancer, lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma.

[0283] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of ahaematologic cancer. The haematologic cancer may be selected from acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia and acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia; or lymphoma including non-Hodgkin lymphoma (NHL), e.g. Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL); or primary effusion lymphoma (PEL).

[0284] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a solid organ cancer. The solid organ cancer may be selected from glioma including low grade glioma and glioblastoma multiforme / astrocytoma; sarcoma including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma; pancreatic cancer including pancreatic ductal adenocarcinoma; bladder carcinoma including urothelial (transitional cell) bladder cancer; hepatocellular carcinoma including adult and paediatric hepatocellular carcinoma and hepatoblastoma; intrahepatic cholangiocarcinoma; gastric cancer including gastric adenocarcinoma; non-small cell lung cancer (NSCLC) including lung adenocarcinoma and lung squamous cell carcinoma; prostate carcinoma including prostate adenocarcinoma; oesophageal squamous cell carcinoma; head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma; neuroblastoma; colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma; cervical cancer including cervical squamous cell carcinoma and cervical adenocarcinoma; adrenocortical carcinoma; breast cancer including breast invasive carcinoma; mesothelioma; ovarian cancer including epithelial ovarian carcinoma; or renal cell carcinoma (RCC) including clear cell renal cell carcinoma (ccRCC).

[0285] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of leukaemia.

[0286] Suitably, the leukaemia may be any of the leukaemias described herein, for example acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia. More suitably the leukaemia is selected from AML leukaemia or chronic myeloid leukaemia.

[0287] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of AML leukaemia.

[0288] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of hepatocellular carcinoma.

[0289] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of METTL1 activity.

[0290] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder in which METTL1 activity is implicated. Suitably, the cancer is selected from solid organ cancer, lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T- ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma.

[0291] The present invention provides a compound, or a pharmaceutically acceptablesalt thereof, as defined herein for use in increasing or enhancing an anti-tumour response to radiotherapy.

[0292] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the inhibition of metastasis in vivo.

[0293] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0294] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cardiac fibrosis.

[0295] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers. Suitably, the cancer is selected from solid organ cancer, lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non- clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma.

[0296] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a haematologic cancer. The haematologic cancer may be selected from acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia and acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia; or lymphoma including non-Hodgkin lymphoma (NHL), e.g. Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL); or primary effusion lymphoma (PEL).

[0297] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a solid organ cancer. The solid organ cancer may be selected from glioma including low grade glioma and glioblastoma multiforme / astrocytoma; sarcoma including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma; pancreatic cancer including pancreatic ductal adenocarcinoma; bladder carcinoma including urothelial (transitional cell) bladder cancer; hepatocellular carcinoma including adult and paediatric hepatocellular carcinoma and hepatoblastoma; intrahepatic cholangiocarcinoma; gastric cancer including gastric adenocarcinoma; non-small cell lung cancer (NSCLC) including lung adenocarcinoma and lung squamous cell carcinoma; prostate carcinoma including prostate adenocarcinoma; oesophageal squamous cell carcinoma; head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma; neuroblastoma; colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma; cervical cancer including cervical squamous cell carcinoma and cervical adenocarcinoma; adrenocortical carcinoma; breast cancer including breast invasive carcinoma; mesothelioma; ovarian cancer including epithelial ovarian carcinoma; or renal cell carcinoma (RCC) including clear cell renal cell carcinoma (ccRCC).

[0298] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of leukaemia.

[0299] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of AML leukaemia.

[0300] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for thetreatment of hepatocellular carcinoma.

[0301] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of METTL1 activity.

[0302] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which METTL1 activity is implicated. Suitably, the disease or disorder in which METTL1 activity is implicated is cancer, such as solid organ cancer, lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T- ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma.

[0303] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for increasing or enhancing an anti-tumour response to radiotherapy.

[0304] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for theinhibition of metastasis in vivo.

[0305] The term "proliferative disorder" are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, non-cancerous / benign tumors (e.g. type ameloblastoma), pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), atherosclerosis and cardiac fibrosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain and skin.

[0306] The anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of METTL1 activity).

[0307] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).

[0308] In a particular embodiment of the invention, the proliferative condition to be treated is cancer. Routes of Administration The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action). Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Combination Therapies

[0309] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.

[0310] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with radiotherapy. Suitably, the compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, is for administration before, during or following the radiotherapy.

[0311] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with chemotherapy. Suitably, the compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, is for simultaneous, separate or sequential administration with the chemotherapy.

[0312] Such chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere (docetaxel) and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example lenvatinib, inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin- 4-amine (CI 1033), erbB2tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00 / 47212), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)]; (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies; (xi) Agents used to treat AML leukaemia, including for example, cytarabine, FLT3 inhibitors, BCL2 inhibitors or IDH1 / 2 inhibitors; (xii) immune oncology agents or therapies (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and / or CAR-T cell therapy)).

[0313] In a particular embodiment, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more of: ● Radiotherapy; ● chemotherapy including Doxorubicin, 5-Fluorouracil (5-FU), Docetaxel, Cisplatin or Etoposide; ● targeted therapies including Lenvatinib and Sorafenib; ● immune checkpoint inhibitors such as PD1 inhibitors and CTLA4 inhibitors.

[0314] In a particular embodiment, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with radiotherapy.

[0315] In a particular embodiment, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with chemotherapy, such as Doxorubicin, 5-Fluorouracil (5-FU), Docetaxel, Cisplatin, Etoposide.

[0316] In a particular embodiment, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with targeted therapies such as those using Lenvatinib and / or Sorafenib.

[0317] In a particular embodiment, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor, such as a PD1 inhibitor or CTLA4 inhibitor.

[0318] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with chemotherapy, such as Doxorubicin, 5-Fluorouracil (5-FU), Docetaxel, Cisplatin, Etoposide. In a particular embodiment, the cancer is hepatocellular carcinoma.

[0319] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with targeted therapies such as those using Lenvatinib and / or Sorafenib. In a particular embodiment, the cancer is hepatocellular carcinoma.

[0320] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0321] According to this aspect of the invention there is provided a combination for use in the treatment of a non-cancerous tumour (for example ameloblastoma) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another anti-tumour agent.

[0322] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another anti-tumour agent.

[0323] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour) or non-cancerous tumour growth (such as ameloblastoma), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and any one of the anti-tumour agents listed herein above.

[0324] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer incombination with another anti-tumour agent, optionally selected from one listed herein above. Suitably, the compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, is for simultaneous, separate or sequential administration with another anti-tumour agent, optionally selected from one listed herein above.

[0325] In a further aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor.

[0326] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with an immune checkpoint inhibitor. Suitably, the compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor.

[0327] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0328] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.

[0329] In another embodiment, the invention relates to a therapeutic combination comprising a compound as defined herein and another agent used to treat AML leukeamia e.g., cytarabine, FLT3 inhibitors, BCL2 inhibitors or IDH1 / 2 inhibitors.

[0330] The combinations described herein may be utilised in the treatment of any of the diseases or disorders described herein. Numbered Paragraphs

[0331] The following paragraphs are not claims, but define particular aspects and embodiments of the invention:Paragraph 1. A compound according to Formula (I) below, or a pharmaceutically acceptable salt thereof:wherein: Ring A is (3-12C)cycloalkyl or 4- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents selected from (1- 6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1, OC(O)RA1, C(O)N(RA1)RA2, N(RA1)C(O)RA2; wherein RA1and RA2are each independently selected from hydrogen or (1-4C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by (1-4C)alkyl; and any (1-6C)alkyl in a substituent on Ring A is optionally further substituted by one or more of halo, cyano, hydroxy or NH2; Ring B is a 5 to 10-membered aryl or heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis a group of the formula: XB-YB-ZBwherein XBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RXaand RXbis independently selected from hydrogen or (1-2C)alkyl; YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, -N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1-2C)alkyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, aryl (e.g. phenyl), heterocyclyl (including a 4 to 7 membered monocyclic heterocyclic or a fused bicyclic heterocyclicring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), heteroaryl (including a monocyclic or bicyclic heteroaryl ring system), C3-8cycloalkyl(1-4C)alkyl, aryl(1-4C)alkyl, heterocyclyl(1-4C)alkyl or heteroaryl(1- 4C)alkyl; and wherein ZBis optionally further substituted by one or more substituents selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-6C)alkyl or (1-6C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl; R1aand R1bare independently selected from hydrogen, (1-2C)alkyl, halo, (1-2C)haloalkyl, with the proviso that at least one of R1aand R1bis not hydrogen; R3a, R3b, R4aand R4bare each independently selected from hydrogen, halo or methyl; R5and R7are each independently selected from hydrogen, halo, hydroxy, methyl or methoxy; R6is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; R8is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; wherein any one or more nitrogen atoms in the compound of Formula (I) is optionally in the form of an N-oxide. Paragraph 2. A compound according to paragraph 1, or a pharmaceutically acceptable salt thereof,wherein Ring A is selected from (5-10C)cycloalkyl or 5- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1or C(O)N(RA1)RA2wherein RA1and RA2are each independently selected from hydrogen or (1-3C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by (1-2C)alkyl.Paragraph 3. A compound according to paragraph 1 or paragraph 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from (5-8C)cycloalkyl (including monocyclic and bridged, fused, or spirocyclic cycloalkyl) or 5- to 8-membered heterocyclyl (including monocyclic, bridged, fused, or spirocyclic heterocyclyl); wherein Ring A is optionally substituted on any available carbon atom by one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, oxo, cyano, NRA1RA2or ORA1, wherein RA1and RA2are each independently selected from hydrogen or (1-2C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by methyl. Paragraph 4. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein either: ,wherein any available carbon atom in the above rings may be optionally substituted by one or more substituents as defined in any one of the preceding paragraphs; and may be optionally substituted on any available nitrogen atom by methyl; and wherein if Ring A is selected from list a), then the atom to which Ring A is attached to in Ring B is a carbon atom; optionally wherein any available carbon atom in the above rings may be optionally substituted by one or more substituents selected from fluoro, chloro, hydroxy, cyano, oxo, (1- 2C)alkyl, (1-2C)alkoxy; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, cyano or hydroxy; and any available nitrogen atom may be optionally substituted by methyl.Paragraph 5. A compound according to any one of the preceding paragraphs, wherein Ring A is selected from:. Paragraph 6. A compound according to paragraph 4 or 5, wherein the nitrogen which links Ring A to Ring B is optionally in the form of an N-oxide, e.g.. Paragraph 7. A compound according to any one of the preceding paragraphs, wherein Ring B is selected from phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis as defined in paragraph 1; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl. Paragraph 8. A compound according to any one of the preceding paragraphs, wherein Ring B is selected from: i) a group with the formula:, wherein: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B3is selected from N or CRB3; B4is selected from S, O, N, NRB4Nor CRB4; B5is selected from N or CRB5; with the proviso that no more than three of the atoms which make up the ring formed by B1, B2,B3,B4and B5are a heteroatom; wherein: each of RB2, RB3, RB4and RB5are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy; and RB2Nand RB4Nare selected from hydrogen or (1-2C)alkyl; ii) a group with the formula:, wherein C2is selected from N or CRC2; C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; C6is selected from N or CRC6; with the proviso that no more than two of C2, C3, C4, C5or C6are nitrogen; wherein each of RC2, RC3, RC4, RC5and RC6, are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy;iii) a group with the formula:D2is selected from N or CRD2; D3is selected from N or CRD3; D4is selected from N or CRD4; D5is selected from N or C; D6is selected from S, O, N, NRD6Nor CRD6; D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising D2, D3, D4, D5, D6, D7, D8and D9are a heteroatom; wherein: each of RD2, RD3, RD6and RD8are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy; RD4and RD7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; RD6Nand RD8Nare selected from hydrogen or (1-4C)alkyl; iv) a group with the formula:Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2;Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Y1, Y2, Y3, Y4, Y5, Y6,Y7, Y8and Y9are a heteroatom; wherein: each of RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy; RY2Nand RY3Nare each independently selected from hydrogen or (1-4C)alkyl; and RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1. Paragraph 9. A compound according to any one of the preceding paragraphs, wherein Ring B is selected from: i) a group with the formula:, wherein: B1, B2, B4and B5are as defined in paragraph 8; ii) a group with the formula:, wherein C2,C4,C5or C6are as defined in paragraph 8; iii) a group with the formula:wherein D2, D4, D5, D7, D8and D9are as defined in paragraph 8; iv) a group with the formula:wherein Y1, Y2, Y4, Y5, Y7, Y8and Y9are as defined in paragraph 8. Paragraph 10. A compound according to paragraph 8 or 9, or a pharmaceutically acceptable salt thereof, wherein: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B4is selected from S, O, N, NRB4Nor CRB4; B5is selected from N or CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; C2is selected from N or CRC2;C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; C6is selected from N or CRC6; with the proviso that no more than one of C2, C3, C4, C5or C6is nitrogen; D2is selected from N or CRD2; D3is selected from N; D4is selected from N or CRD4; D5is selected from N or C; D6is selected from S, O, N, NRD6Nor CRD6; D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; with the proviso that the 9-membered bicyclic ring comprising D2, N, D4, D5, D6, D7, D8and D9comprises no more than 4 heteroatoms in the ring structure; Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, Y6, Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2Nand RY3Nare each independently as defined in paragraph 8. Paragraph 11. A compound according to paragraph 8, 9 or 10, wherein: B1is selected from N or C; B2is CRB2;B4is selected from S, NRB4Nor CRB4; B5is CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; C2is selected from N or CRC2; C4is CRC4; C5is selected from N or CRC5; C6is CRC6; with the proviso that no more than one of C2, C4, C5or C6is nitrogen; D2is CRD2; D3is N; D4is CRD4; D5is selected from C; D6is selected from S, O or N; D7is selected from N, CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; with the proviso that the 9-membered bicyclic ring comprising D2, N, D4, D5, N, D7, D8and D9comprises no more than 4 heteroatoms in the ring structure; Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, N,Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2Nand RY3Nare independently as defined in paragraph 8.Paragraph 12. A compound according to any one of paragraphs 8 to 11, or a pharmaceutically acceptable salt thereof, wherein: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy; RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare selected from hydrogen or methyl; RD4, RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; preferably wherein: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen or halo, preferably hydrogen; RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare independently selected from hydrogen or methyl; RD4is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; more preferably wherein: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD3, RD6, RD8, RY2, RY3, RY5, RY6and RY8are hydrogen; RD2is selected from hydrogen or halo, e.g. fluoro, chloro or bromo; RB2N, RB4NRD6N, RD8N, RY2Nand RY3Nare independently selected from hydrogen or methyl; RD4is selected from hydrogen, fluoro, bromo, iodo, cyano or methyl; RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1. Paragraph 13. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from: i) a group with a formula selected from:, wherein: RB2is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RB4is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RB5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; ii) a group with a formula selected from:wherein: RC2is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC4is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy;iii) a group with a formula selected from:wherein: RD2, RD3and RD8are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3);RD4is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; wherein RBis as defined in any one of the preceding paragraphs; and RD8Nis selected from hydrogen or (1-4C)alkyl; iv) a group with a formula selected from: ,wherein: RY2is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RY5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of the preceding paragraphs; and RY8is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl (e.g. CF3) or fluoromethoxy (e.g. OCF3).Paragraph 14. A compound according to paragraph 13, or a pharmaceutically acceptable salt thereof, wherein: RB2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RB4is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RB5is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC4is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC5is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RD2is selected from hydrogen or halo (e.g. fluoro or chloro); RD3and RD8are independently selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RD4is selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; RY2independently selected from hydrogen or halo (e.g. fluoro or chloro); RY5independently selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; RY8independently selected from hydrogen or halo (e.g. fluoro or chloro). Paragraph 15. A compound according to paragraph 13 or 14, or a pharmaceutically acceptable salt thereof, wherein: RB2is selected from hydrogen or halo; RB4is selected from hydrogen or halo; RB5is selected from hydrogen or halo; RC2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC4is selected from hydrogen or halo; RC5is selected from hydrogen or halo; RC6is selected from hydrogen or halo;RD2is selected from hydrogen or halo; RD3is selected from hydrogen or halo; RD4is selected from hydrogen, fluoro, bromo, iodo, cyano or methyl; RD7is selected from hydrogen, halo, cyano or a group RB; RD8is selected from hydrogen or halo; RY2is selected from hydrogen or halo; RY5is selected from hydrogen or halo; RY8is selected from hydrogen or halo; RY7is selected from hydrogen, halo, cyano or a group RB; wherein RBis as defined in paragraph 1. Paragraph 16. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:, , ,wherein RD4, RD7and RY7are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1. Paragraph 17. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:wherein: RD4is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; preferably RD4is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano or methyl;RD7and RY7are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1; preferably wherein Ring B is:wherein RD7is independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in paragraph 1. Paragraph 18. A compound according to any one of the preceding paragraphs, wherein one or more of the nitrogen atoms which make up Ring B is optionally in the form of an N-oxide. Paragraph 19. A compound according to any one of paragraphs 7 to 18, wherein any nitrogen in the “D3” position in Ring B is optionally in the form of an N-oxide, e.g.:. Paragraph 20. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RXaand RXbis independently selected from hydrogen or methyl; YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -N(RY1)-, -N(RY1)- C(O)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclic ring system, 5 to 9-membered spirocyclic heterocyclic ring system, or 5 to 9-membered bridged heterocyclic ring system or a monocyclic or bicyclic heteroaryl ring system, phenyl, 5- to 10-membered heteroaryl, C3-8cycloalkyl(1-4C)alkyl, phenyl(1-4C)alkyl, (4 to 9- membered)heterocyclyl(1-4C)alkyl or (4 to 9-membered)heteroaryl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1or C(O)ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; wherein if XBand YBare absent, then ZBis not hydrogen. Paragraph 21. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein RBis is a group of the formula: XB-YB-ZBwherein XBis absent or [CH2]n, wherein n is an integer from 1 to 2; YBis absent or selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclyl, 5 to 9-membered spirocyclic heterocyclyl, 5 to 9-membered bridged heterocyclyl, a monocyclic or bicyclic heteroaryl, phenyl, C3-8cycloalkyl(1-4C)alkyl, (4 to 7 membered monocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered fused bicyclic)heterocyclyl(1- 4C)alkyl, (5 to 9-membered spirocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-memberedbridged)heterocyclyl(1-4C)alkyl, (monocyclic or bicyclic)heteroaryl(1-4C)alkyl, or phenyl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, oxo, cyano, hydroxy, NH2or methyl; wherein if XBand YBare absent, then ZBis not hydrogen. Paragraph 22. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CH2]; YBis selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclyl, 5 to 9-membered spirocyclic heterocyclyl, 5 to 9-membered bridged heterocyclyl, a monocyclic or bicyclic heteroaryl, phenyl, C3-8cycloalkyl(1-4C)alkyl, (4 to 7 membered monocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered fused bicyclic)heterocyclyl(1- 4C)alkyl, (5 to 9-membered spirocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered bridged)heterocyclyl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; preferably wherein RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CH2];YBis selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, C3-8cycloalkyl(1-3C)alkyl or (4 to 7 membered monocyclic)heterocyclyl(1- 3C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from methyl, halo, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl. Paragraph 23. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein RBis a group with a formula selected from:, , , , ,,Paragraph 24. A compound according to any one of the preceding paragraphs, wherein R1ais hydrogen and R1bis methyl. Paragraph 25. A compound according to any one of the preceding paragraphs, wherein R3a, R3b, R4aand R4bare each independently selected from hydrogen or halo; preferably R3a, R3b, R4aand R4bare each hydrogen. Paragraph 26. A compound according to any one of the preceding paragraphs, wherein: i) R5is selected from hydrogen, halo or methoxy; preferably R5is hydrogen; and / or ii) R7is selected from hydrogen, halo, hydroxy or methoxy; preferably R7is hydrogen or hydroxy; further preferably R7is hydrogen. Paragraph 27. A compound according to any one of the preceding paragraphs, wherein R6is selected from hydrogen, hydroxy, methyl, halo, methoxy, fluoromethyl (e.g. CF3, CHF2, CHF2) or fluoromethoxy (e.g. OCF3, OCHF2, OCH2F).Paragraph 28. A compound according to any one of the preceding paragraphs, wherein R6is selected from hydrogen, fluoro, chloro or fluoromethyl; preferably wherein R6is selected from fluoro, chloro or trifluoromethyl. Paragraph 29. A compound according to any one of the preceding paragraphs, wherein R8is selected from hydrogen, hydroxy, methyl, halo, methoxy, fluoromethyl or fluoromethoxy. Paragraph 30. A compound according to any one of the preceding paragraphs, wherein R8is selected from hydrogen, fluoro, chloro, bromo or trifluoromethyl; preferably wherein R8is selected from hydrogen, fluoro or chloro; more preferably wherein R8is selected from hydrogen or chloro. Paragraph 31. A compound according to any one of the preceding paragraphs, wherein the compound is of Formula (Ia), (Ib), (Ic), (IIa), (IIb) or (IIc) below:wherein Ring A, Ring B, R1a, R1b, R6, R8, RD2, RD4and RD7are as defined in any one of the preceding paragraphs. Paragraph 32. A compound selected from: (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(3-(pyridin-3-yl)piperidin-1- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)piperazin-2- yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)(6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)piperidin-3-yl)(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)pyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (3-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-azabicyclo[3.1.0]hexan-1-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)thiomorpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-methylmorpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6-chloro-8-fluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-8-fluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-6-fluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;((1R,4R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (methylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((3R,6S)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1-methylpiperazin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-((cyclopropylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- hydroxyethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methoxypyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((5R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4RS)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4SR)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,5-difluoropiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-(cyclopropylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-(ethylamino)oxazolo[4,5- c]pyridin-7-yl)morpholin-2-yl)methanone;((R)-4-(2-((cyclobutylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(piperidin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(6,8-dichloro-1,1-dimethyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)morpholin-2- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3-yl)morpholin-2- yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-6,6-dimethyl-4-(pyridin-3- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyrimidin-5-yl)morpholin-2- yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(imidazo[1,2-a]pyrazin-5- yl)morpholin-2-yl)methanone ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-methyloxazolo[4,5- c]pyridin-7-yl)morpholin-2-yl)methanone; rac-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3- yl)thiomorpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-4-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;(4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-7-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-6-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(isothiazol-4-yl)morpholin-2- yl)methanone; ((R)-4-([1,2,4]triazolo[4,3-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-1-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(1-(pyridin-3-yl)pyrrolidin-3- yl)methanone;((1R,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3S)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(6-aminoimidazo[1,2-a]pyrazin-3-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2RS,4RS)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-2-oxabicyclo[2.1.1]hexan-1-yl)(6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4,6-dibromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-methyloxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; N-(7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)acetamide; ((R)-4-(2-amino-4,6-dichlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; or ((R)-4-(2-amino-6-chlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; or a pharmaceutically acceptable salt thereof. Paragraph 33. A pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.Paragraph 34. A combination comprising a compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. Paragraph 35. A compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to paragraph 33, or a combination according to paragraph 34, for use in therapy. Paragraph 36. A compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to paragraph 33, or a combination according to paragraph 34, for use in the treatment of a proliferative condition, for example cancer. Paragraph 37. A compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to paragraph 33, or a combination according to paragraph 34, for use in the treatment of cancer; preferably wherein the cancer is selected from solid organ cancer, lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T- ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colonadenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma. Paragraph 38. A compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to paragraph 33, or a combination according to paragraph 34, for use in the treatment of leukaemia; preferably the leukaemia is selected from: ● acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; ● chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; ● acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); and ● chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia; more preferably the leukaemia is selected from AML leukaemia or chronic myeloid leukaemia. Paragraph 39. A compound according to any one of paragraphs 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to paragraph 33, or a combination according to paragraph 34, for use in the inhibition of METTL1 activity. EXAMPLES Compounds of Formula (I) can be prepared in accordance with synthetic methods known to one skilled in the art. The invention also provides methods for the preparation of compounds defined in Formulas (I) above. Where intermediates were commercially available or previously exemplified, these were identified using databases such as SciFinder, where intermediates were not commercially available, the synthesis is detailed herein using standard transformations. Commercial reagents were used without further purification. Where racemic mixtures of compounds have been separated by chiral chromatography, the stereochemistry has been inferred by reference to comparisons of biological activity to compounds where the stereochemistry is known and / or by x-ray crystallography of compound-METTL1 protein complexes. General Procedures Room temperature (RT) refers to ambient temperatures of approximately 20 – 27 °C.1H NMR spectra were recorded at either 400 MHz or 500 MHz at either ambient temperature or 353 Kusing an internal deuterium lock. Chemical shift values are reported in parts per million (ppm) using an internal deuterium lock. Standard abbreviations are used throughout (s singlet; br broad; d doublet; dd doublet of doublets; t triplet; q quartet; quin quintet; m multiplet). Coupling constants are reported in Hertz (Hz). Chromatography refers to column chromatography performed using silica or C18 silica under positive pressure (flash chromatography) conditions. LCMS Methods LCMS experiments were carried out using electrospray conditions under the conditions below. (Solvents A1 = 0.1% HCO2H in H2O; A2 = 2 mM ammonium acetate and 0.1% HCO2H in H2O; A3 = 2 mM ammonium bicarbonate in water, buffered to pH 10; A4 = 0.2% NH4OH in water; A5 = 0.1% TFA in water; A6 = 10 mM ammonium bicarbonate in water; A7 = 0.04% TFA in water; A8 = 5 mM ammonium bicarbonate in water; A9 = 0.05% HCO2H in H2O; A10 = 0.05% TFA in water; A11 = 0.02% TFA in water; B1 = 0.1% HCO2H in MeCN:H2O (90:10); B2 = 0.1% HCO2H in MeCN; B3 = MeCN; B4 = 0.1% TFA in MeCN; B5 = 0.02% TFA in MeCN; B6 = MeCN:MeOH:IPA (65:25:10)...

Claims

CLAIMS 1. A compound according to Formula (I) below, or a pharmaceutically acceptable salt thereof:wherein: Ring A is (3-12C)cycloalkyl or 4- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1, OC(O)RA1, C(O)N(RA1)RA2, N(RA1)C(O)RA2; wherein RA1and RA2are each independently selected from hydrogen or (1-4C)alkyl; and Ring A may be optionally substituted on any available nitrogen atom by (1-4C)alkyl; and any (1-6C)alkyl in a substituent on Ring A is optionally further substituted by one or more of halo, cyano, (1-4C)alkoxy, hydroxy or NH2; wherein Ring A is optionally fused to a phenyl ring or a 5- or 6-membered heteroaryl ring, wherein the phenyl ring or a 5- or 6-membered heteroaryl ring may in turn be optionally substituted by one or more substituents selected from from (1-6C)alkyl, halo, (1-6C)- haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-4C)alkyl; Ring B is a 5 to 10-membered aryl or heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis a group of the formula: XB-YB-ZBwhereinXBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RXaand RXbis independently selected from hydrogen or (1-2C)alkyl; YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, -N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1-2C)alkyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, aryl (e.g. phenyl), heterocyclyl (including a 4 to 7 membered monocyclic heterocyclic or a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), heteroaryl (including a monocyclic or bicyclic heteroaryl ring system), C3- 8cycloalkyl(1-4C)alkyl, aryl(1-4C)alkyl, heterocyclyl(1-4C)alkyl or heteroaryl(1- 4C)alkyl; and wherein ZBis optionally further substituted by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-6C)alkyl or (1-6C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl; R1aand R1bare independently selected from hydrogen, (1-2C)alkyl, halo, (1-2C)haloalkyl, with the proviso that at least one of R1aand R1bis not hydrogen; R3a, R3b, R4aand R4bare each independently selected from hydrogen, halo or methyl; R5and R7are each independently selected from hydrogen, halo, hydroxy, methyl or methoxy; R6is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; R8is selected from selected from hydrogen, hydroxy, cyano, amino, (1-4C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; and wherein any one or more nitrogen atoms in the compound of Formula (I) is optionally in the form of an N-oxide; with the proviso that the compound is not:4-(6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-[4-(4- methylpiperidin-1-yl)phenyl]pyrrolidine-2-one; or [1-(5,6-dimethylthieno[3,2-e]pyrimidin-4-yl)piperidin-4-yl]-(7-fluoro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl)methanone.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from (5-10C)cycloalkyl or 5- to 12-membered heterocyclyl; wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-3C)alkyl; wherein any (1-3C)alkyl is optionally further substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and Ring A may be optionally substituted on any available nitrogen atom by (1-2C)alkyl; wherein Ring A is optionally fused to a phenyl ring or a 6-membered heteroaryl ring, wherein the phenyl ring or 6-membered heteroaryl ring may in turn be optionally substituted by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-3C)alkyl. optionally wherein Ring A is selected from (5-8C)cycloalkyl (including monocyclic and bridged, fused, or spirocyclic cycloalkyl) or 5- to 8-membered heterocyclyl (including monocyclic, bridged, fused, or spirocyclic heterocyclyl); wherein Ring A is optionally substituted on any available carbon atom by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, oxo, cyano, ORA1, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-2C)alkyl; wherein any (1-2C)alkyl is optionally substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and Ring A may be optionally substituted on any available nitrogen atom by methyl; wherein Ring A is optionally fused to a phenyl ring which may in turn be optionally substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)ORA3or C(O)N(RA3)RA4, wherein RA3and RA4are each independently selected from hydrogen or (1-2C)alkyl; further optionally wherein Ring A is selected from (5-8C)cycloalkyl (including monocyclic and bridged, fused, or spirocyclic cycloalkyl) or 5- to 8-membered heterocyclyl (including monocyclic, bridged, fused, or spirocyclic heterocyclyl); wherein Ring A is optionally substituted on any available carbon atom by one or more substituents selected from fluoro, chloro, hydroxy, oxo, (1-2C)alkyl, (1-2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, methoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; wherein Ring A is optionally fused to a phenyl ring which may in turn be optionally substituted by one or more substituents selected from methyl, fluoro, cyano, NRA3RA4or ORA3, wherein RA3and RA4are each independently selected from hydrogen or methyl.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein either: a) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Ring A1, A2, A3 or A4 are selected from saturated or partially saturated monocyclic, bridged, fused, or spirocyclic (5-10C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 5- to 10-membered heterocyclyl;wherein bonds a1, a2, a3 and a4 are either a single or a double bond; wherein any of Ring A1, A2, A3 or A4 may be optionally fused to a phenyl ring or a 5- or 6-membered heteroaryl ring; b) Ring A has a structure according to Ring A5:wherein Ring A5 is selected from a monocyclic (7C)cycloalkyl, a monocyclic 7-membered heterocyclyl, a bridged, fused, or spirocyclic (7-10C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 7- to 10-membered heterocyclyl; c) Ring A is a spirocylic ring according to Ring A6 shown below,:wherein in Ring A6, Ring A6a is a (3-6C)cycloalkyl or 4-7 membered heterocylic ring, and Ring A6b is a 4-7membered heterocyclic ring, wherein Ring A6a is spiro-fused to Ring A6b; wherein any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available carbon atom by one or more substituents independently selected from (1-6C)alkyl, halo, (1-6C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1, OC(O)RA1, C(O)N(RA1)RA2, N(RA1)C(O)RA2; wherein RA1and RA2are each independently selected from hydrogen or (1-4C)alkyl; and Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available nitrogen atom by (1-4C)alkyl;and any (1-6C)alkyl in a substituent on Ring A is optionally further substituted by one or more of halo, cyano, (1-4C)alkoxy, hydroxy or NH2; and any phenyl or heteroaryl ring fused to Ring A1, A2, A3 or A4 may be optionally substituted by one or more substituents selected from from (1- 6C)alkyl, halo, (1-6C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-4C)alkyl; and wherein if Ring A is selected from Ring A1, A5 or A6, then the atom to which Ring A is attached to in Ring B is a carbon atom.

4. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein either: a) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Ring A1, A2, A3 or A4 are selected from saturated or partially saturated monocyclic, bridged, fused, or spirocyclic (5-8C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 5- to 8-membered heterocyclyl; wherein bonds a1, a2, a3 and a4 are either a single or a double bond; andwherein any of Ring A1, A2, A3 or A4 may be optionally fused to a phenyl ring or a 6-membered heteroaryl ring; b) Ring A has a structure according to Ring A5:wherein Ring A5 is selected from a monocyclic (7C)cycloalkyl or a monocyclic 7-membered heterocyclyl; or c) Ring A is a spirocylic ring according to Ring A6 shown below,:wherein in Ring A6, Ring A6a is a (3-6C)cycloalkyl or 4- to 6-membered heterocylic ring, and Ring A6b is a 4-7 membered heterocyclic ring, wherein Ring A6a is spiro-fused to Ring A6b; wherein any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available carbon atom by one or more substituents independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, oxo, cyano, NRA1RA2, ORA1, C(O)RA1, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-3C)alkyl; wherein any (1-3C)alkyl is optionally further substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available nitrogen atom by (1-2C)alkyl; and any phenyl or heteroaryl ring fused to Ring A1, A2, A3 or A4 may be optionally substituted by one or more substituents independently selected from (1-3C)alkyl, halo, (1- 3C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-3C)alkyl;and wherein if Ring A is selected from Ring A1, A5 or A6, then the atom to which Ring A is attached to in Ring B is a carbon atom.

5. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein either: a) Ring A is selected from a ring with a structure according to Ring A1, A2, A3 or A4;wherein Ring A1, A2, A3 or A4 are selected from saturated or partially saturated monocyclic, bridged, fused, or spirocyclic (5-8C)cycloalkyl or saturated or partially saturated monocyclic, bridged, fused, or spirocyclic 5- to 8-membered heterocyclyl; wherein bonds a2, a3 and a4 are either a single or a double bond; and wherein any of Ring A1, A2, A3 or A4 may be optionally fused to a phenyl ring; b) Ring A has a structure according to Ring A5:wherein Ring A5 is selected from a monocyclic (7C)cycloalkyl or a monocyclic 7-membered heterocyclyl; orc) Ring A is a spirocylic ring according to Ring A6 shown below,:Ring A6 wherein, in Ring A6, Ring A6a is a (3-4C)cycloalkyl, and Ring A6b is a 5- or 6-membered heterocyclic ring, wherein Ring A6a is spiro-fused to Ring A6b; wherein any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available carbon atom by one or more substituents selected from fluoro, chloro, hydroxy, oxo, (1-2C)alkyl, (1-2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, methoxy or hydroxy; and any of Ring A1, A2, A3, A4, A5, A6a and A6b may be optionally substituted on any available nitrogen atom by methyl; and any phenyl ring fused to one of Ring A1, A2, A3 and A4 may be optionally substituted by one or more substituents selected from methyl, fluoro, cyano, NRA3RA4or ORA3, wherein RA3and RA4are each independently selected from hydrogen or methyl; and wherein if Ring A is selected from Ring A1, A5 or A6, then the atom to which Ring A is attached to in Ring B is a carbon atom.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein one of the following applies: a) Ring A is selected from:, ,wherein any available carbon atom in the above rings may be optionally substituted on any available carbon atom by one or more substituents as defined in any one of the preceding claims; and may be optionally substituted on any available nitrogen atom by methyl; and wherein if Ring A is selected from list a), then the atom to which Ring A is attached to in Ring B is a carbon atom.

7. A compound according to claim 6, wherein any available non-aromatic carbon atom in the ring defined in claim 6 may be optionally substituted on any available carbon atom by one or more substituents selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkyl, (1- 2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; and any available aromatic carbon atom in a ring defined in claim 6 may be optionally substituted by a substituent independently selected from (1-3C)alkyl, halo, (1-3C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)RA3, C(O)ORA3or C(O)N(RA3)RA4wherein RA3and RA4are each independently selected from hydrogen or (1-3C)alkyl;optionally wherein any available non-aromatic carbon atom in the ring defined in claim 6 may be optionally substituted by one or more substituents independently selected from (1-2C)alkyl, (1-2C)alkoxy, halo, (1-2C)haloalkyl, oxo, cyano, ORA1, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1and RA2are each independently selected from hydrogen or (1-2C)alkyl; wherein any (1-3C)alkyl or (1-3C)alkoxy is optionally substituted by one or more substituents selected from fluoro, cyano, (1-2C)alkoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; and any available aromatic carbon atom in a ring defined in claim 6 may be optionally substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1- 2C)haloalkyl, cyano, NRA3RA4, ORA3, C(O)ORA3or C(O)N(RA3)RA4, wherein RA3and RA4are each independently selected from hydrogen or (1-2C)alkyl. further optionally wherein any available non-aromatic carbon atom in the ring defined in claim 6 may be optionally substituted by one or more substituents selected from fluoro, chloro, hydroxy, oxo, (1-2C)alkyl, (1-2C)alkoxy, NRA1RA2, C(O)ORA1or C(O)N(RA1)RA2, wherein RA1are each independently selected from hydrogen or methyl; wherein any (1- 2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more substituents selected from fluoro, methoxy or hydroxy; and any available nitrogen atom may be optionally substituted by methyl; and any available aromatic carbon atom in a ring defined in claim 6 may be optionally substituted by a substituent selected from methyl, fluoro, cyano, NRA3RA4or ORA3, wherein RA3and RA4are each independently selected from hydrogen or methyl.

8. A compound according to any one of the preceding claims, wherein Ring A is selected from:further optionally wherein Ring A is:.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; wherein any available carbon atom on Ring B is optionally substituted by halo, oxo, cyano or a group RB; wherein RBis as defined in claim 1; and any available nitrogen atom in Ring B is optionally substituted by (1-2C)alkyl.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from: i) a group with the formula:, wherein: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B3is selected from N or CRB3; B4is selected from S, O, N, NRB4Nor CRB4; B5is selected from N or CRB5; with the proviso that no more than three of the atoms which make up the ring formed by B1, B2,B3,B4and B5are a heteroatom; wherein: each of RB2, RB3, RB4and RB5are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy; and RB2Nand RB4Nare selected from hydrogen or (1-2C)alkyl; and ii) a group with the formula:, wherein: C2is selected from N or CRC2; C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; C6is selected from N or CRC6; with the proviso that no more than two of C2, C3, C4, C5or C6are nitrogen;wherein each of RC2, RC3, RC4and RC5are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl or a 4- to 7 membered heterocyclyl; iii) a group with a formula selected from:wherein: D2is selected from N or CRD2; D3is selected from N or CRD3; D4is selected from N or CRD4; D5is selected from N or C; D6is selected from S, O, N, NRD6Nor CRD6; D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; RN3is selected from hydrogen or (1-2C)alkyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising D2, D3, D4, D5, D6,D7, D8and D9are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O), D5, D6,D7, D8and D9are a heteroatom; wherein: each of RD2, RD3, RD6and RD8are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy;RD4and RD7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; RD6Nand RD8Nare selected from hydrogen or (1-4C)alkyl; iv) a group with the formula:wherein: Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Y1, Y2, Y3, Y4, Y5, Y6,Y7, Y8and Y9are a heteroatom; wherein: each of RY2, RY3, RY5, RY6and RY8are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy; RY2Nand RY3Nare each independently selected from hydrogen or (1-4C)alkyl; and RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; or v) a group with a formula selected from:wherein: Z2is selected from N or CRZ2; Z3is selected from N or CRZ3; Z4is selected from N or CRZ4; Z5is selected from N or C; Z6is selected from N or CRZ6; Z7is selected from N or CRZ7; Z8is selected from N or CRZ8; Z9is selected from N or CRZ9; Z10is selected from N or C; RN7is selected from hydrogen or (1-2C)alkyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, C(O), N(RN7), C(O), Z8, Z9and Z10are a heteroatom wherein: each of RZ2, RZ3, RZ4, RZ6and RZ9are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1- 4C)haloalkoxy RZ7and RZ8are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; optionally wherein Ring B is selected from: i) a group with the formula:, ii) a group with the formula:iii) a group with the formula:iv) a group with the formula:v) a group with a formula selected from:.

11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein: B1is selected from N or C; B2is selected from S, O, N, NRB2Nor CRB2; B4is selected from S, O, N, NRB4Nor CRB4; B5is selected from N or CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; C2is selected from N or CRC2; C3is selected from N or CRC3; C4is selected from N or CRC4; C5is selected from N or CRC5; C6is selected from N or CRC6; with the proviso that no more than one of C2, C3, C4, C5or C6is nitrogen; D2is selected from N or CRD2; D3is selected from N; D4is selected from N or CRD4; D5is selected from N or C;D6is selected from S, O, N, NRD6Nor CRD6; D7is selected from N or CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; RN3is selected from hydrogen or methyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising D2, N, D4, D5, N,D7, D8and D9are a 4 heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O), D5, D6, D7, D8and D9are a heteroatom; Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5; Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, Y6, Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; Z2is selected from N or CRZ2; Z3is selected from N or CRZ3; Z4is selected from N or CRZ4; Z5is selected from N or C; Z6is selected from N or CRZ6; Z7is selected from N or CRZ7; Z8is selected from N or CRZ8; Z9is selected from N or CRZ9; Z10is selected from N or C; RN7is selected from hydrogen or (1-2C)alkyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6,Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, N(RN7), C(O), Z8, Z9and Z10are a heteroatom;wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8, RZ9, RN3and RN7are independently as defined in claim 5; optionally wherein: B1is selected from N or C; B2is CRB2; B4is selected from S, NRB4Nor CRB4; B5is CRB5; with the proviso that the 5-membered ring formed by B1, B2, N, B4and B5comprises no more than 3 heteroatoms in the ring structure; C2is selected from N or CRC2; C4is CRC4; C5is selected from N or CRC5; C6is CRC6; with the proviso that no more than one of C2, C4, C5or C6is nitrogen; D2is CRD2; D3is N; D4is CRD4; D5is selected from C; D6is selected from S, O or N; D7is selected from N, CRD7; D8is selected from S, O, N, NRD8Nor CRB8; D9is selected from N or C; RN3is selected from hydrogen or methyl with the proviso that no more than four of the atoms which make up the bicyclic ring comprising D2, N, D4, D5, N, D7, D8and D9are a 4 heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising D2, N(RN3), C(O), D5, D6,D7, D8and D9are a heteroatom; Y1is selected from N or C; Y2is selected from S, O, N, NRY2Nor CRY2; Y3is selected from S, O, N, NRY3Nor CRY3; Y4is selected from N or C; Y5is selected from N or CRY5;Y6is selected from N or CRY6; Y7is selected from N or CRY7; Y8is selected from N or CRY8; Y9is selected from N or C; with the proviso that the 9-membered bicyclic ring formed by Y1, Y2, N, Y4, Y5, N,Y7, Y8and Y9comprises no more than 4 heteroatoms in the ring structure; Z2is CRZ2; Z3is selected from N or CRZ3; Z4is selected from N or CRZ4; Z5is C; Z6is selected from N or CRZ6; Z7is selected from N or CRZ7; Z8is CRZ8; Z9is CRZ9; Z10is C; and RN7is selected from hydrogen or methyl; with the proviso that no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9and Z10are a heteroatom; and no more than four of the atoms which make up the bicyclic ring comprising Z2, Z3, Z4, Z5, N(RN7), C(O), Z8, Z9and Z10are a heteroatom; wherein each of RB2, RB3, RB4, RB5, RC2, RC3, RC4, RC5, RC6, RD2, RD3, RD4, RD6, RD7, RD8, RY2, RY3, RY5, RY6, RY7, RY8, RB2N, RB4N, RD6N, RD8N, RY2N, RY3N,RZ2, RZ3, RZ4, RZ6, RZ7, RZ8and RZ9are independently as defined in claim 5; further optionally wherein: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RZ2, RZ3, RZ6and RZ9RY8are independently selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy; RC6is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy, (4-6C)cycloalkyl or a 5- to 6 membered heterocyclyl; RB2N, RB4NRD6N, RD8N, RY2N, RY3N, RN3RN7are selected from hydrogen or methyl; and RD4, RD7, RY7, RZ4, RZ7and RZ8are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1.

12. A compound according to claim 10 or 11, or a pharmaceutically acceptable salt thereof, wherein: RB2, RB3, RB4, RB5RC2, RC3, RD2, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RZ2, RZ3, RZ6and RZ9are independently selected from hydrogen or halo, preferably hydrogen; RC4and RC5are independently selected from hydrogen, halo or methoxy, preferably hydrogen or methoxy; RC6is selected from hydrogen, halo or a 6 membered monocyclic heterocyclyl; RB2N, RB4NRD6N, RD8N, RY2N, RY3N, RN3and RN7are independently selected from hydrogen or methyl; RD4is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; each of RZ2, RZ3, and RZ9are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RZ4is selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; RZ6is selected from hydrogen, halo or hydroxy, methyl, methoxy or fluoromethyl (e.g. CF3); and one of RZ7and RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3, and the other is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; optionally wherein: RB2, RB3, RB4, RB5RC2, RC3, RC4, RC5, RC6, RD3, RD6, RD8, RY2, RY3, RY5, RY6, RY8, RZ2, RZ3, RZ6and RZ9are hydrogen; RD2is selected from hydrogen or halo, e.g. fluoro, chloro or bromo; RB2N, RB4NRD6N, RD8N, RY2N, RY3N, RN3and RN7are independently selected from hydrogen or methyl; RD4and RZ4are selected from hydrogen, fluoro, bromo, iodo, cyano or methyl;RD7and RY7are each independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; and one of RZ7and RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3, and the other is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from: i) a group with a formula selected from:, wherein: RB2is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RB4is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RB5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; ii) a group with a formula selected from:wherein: RC2is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC3is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC4is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; RC5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RC6is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (3-6C)cycloalkyl or a 4- to 7 membered heterocyclyl;iii) a group with a formula selected from: , ,wherein:RD2, RD3and RD8are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RD4is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; wherein RBis as defined in any one of the preceding claims; and RD8Nis selected from hydrogen or (1-4C)alkyl; iv) a group with a formula selected from: ,wherein: RY2is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RY5is selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl or (1-4C)haloalkoxy; and RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in any one of the preceding claims; andRY8is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl (e.g. CF3) or fluoromethoxy (e.g. OCF3); or v) a group with the formula selected from:wherein: each of RZ2, RZ3, RZ6and RZ9are independently selected from hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl or (1-4C)haloalkoxy; RZ4, RZ7and RZ8are independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; and RN7is selected from hydrogen or methyl; optionally wherein: RB2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RB4is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RB5is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy;RC2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC3is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC4is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC5is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC6is selected from hydrogen, halo, cyano, hydroxy, methyl, methoxy, fluoromethyl or fluoromethoxy, (4-6C)cycloalkyl or a 5- to 6 membered heterocyclyl; RD2is selected from hydrogen or halo (e.g. fluoro or chloro); RD3and RD8are independently selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RD4is selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; RD7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; RY2independently selected from hydrogen or halo (e.g. fluoro or chloro); RY5independently selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RY7is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1; RY8independently selected from hydrogen or halo (e.g. fluoro or chloro); each of RZ2, RZ3, RZ6and RZ9are independently selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3); RZ4is selected from is selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; RZ6is selected from hydrogen, halo, hydroxy, methyl, methoxy or fluoromethyl (e.g. CF3); one of RZ7and RZ8is selected from hydrogen, halo, methyl, methoxy or fluoromethyl (e.g. CF3, and the other is selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1.

14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein:RB2is selected from hydrogen or halo; RB4is selected from hydrogen or halo; RB5is selected from hydrogen or halo; RC2is selected from hydrogen, halo, cyano, hydroxy, methyl or methoxy; RC3is selected from hydrogen or halo RC4is selected from hydrogen, halo or methoxy; RC5is selected from hydrogen, halo or methoxy; RC6is selected from hydrogen, halo or 6 membered heterocyclyl; RD2is selected from hydrogen or halo; RD3is selected from hydrogen or halo; RD4is selected from hydrogen, fluoro, bromo, iodo, hydroxy, cyano or methyl; RD7is selected from hydrogen, halo, cyano or a group RB; RD8is selected from hydrogen or halo; RY2is selected from hydrogen or halo; RY5is selected from hydrogen or halo; RY8is selected from hydrogen or halo; RY7is selected from hydrogen, halo, cyano or a group RB; RZ2is selected from hydrogen or halo; RZ3is selected from hydrogen or halo; RZ4is selected from hydrogen, fluoro, bromo, iodo, cyano or methyl; RZ6is selected from hydrogen, halo or hydroxy; one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; and RZ9is selected from hydrogen or halo;wherein RBis as defined in claim 1.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:,wherein: RC3, RC4, RC5and RC6are as defined in any one of the preceding claims; and RD4, RZ4, RD7and RY7are independently selected from hydrogen, halo, cyano or a group RB; one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; wherein RBis as defined in claim 1; optionally wherein Ring B is selected from:wherein: wherein RBis as defined in claim 1; RC3, RC4, RC5and RC6are as defined in any one of the preceding claims; RZ4and RD4are selected from hydrogen, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; preferably RD4is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano or methyl; RD7and RY7are selected from hydrogen, halo, cyano or a group RB; one of RZ7and RZ8is selected from hydrogen or halo, and the other is selected from hydrogen, halo, cyano or a group RB; andwherein RBis as defined in claim 1; further optionally wherein Ring B is:wherein RD7is independently selected from hydrogen, halo, cyano or a group RB, wherein RBis as defined in claim 1.

16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the nitrogen which links Ring A to Ring B is optionally in the form of an N-oxide, e.g.one or more of the nitrogen atoms which make up Ring B is optionally in the form of an N- oxide; optionally any nitrogen in the “D3” position in Ring B is optionally in the form of an N- oxide, e.g.:.

17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CRXaRXb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RXaand RXbis independently selected from hydrogen or methyl; YBis absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -N(RY1)-, -N(RY1)- C(O)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclic ring system, 5 to 9-membered spirocyclic heterocyclic ring system, or 5 to 9-membered bridged heterocyclic ring system or a monocyclic or bicyclic heteroaryl ring system, phenyl, 5- to 10-membered heteroaryl, C3-8cycloalkyl(1-4C)alkyl, phenyl(1-4C)alkyl, (4 to 9- membered)heterocyclyl(1-4C)alkyl or (4 to 9-membered)heteroaryl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1or C(O)ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1- 2C)alkyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2or methyl; wherein if XBand YBare absent, then ZBis not hydrogen; optionally wherein RBis is a group of the formula: XB-YB-ZBwherein XBis absent or [CH2]n, wherein n is an integer from 1 to 2; YBis absent or selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclyl, 5 to 9-membered spirocyclicheterocyclyl, 5 to 9-membered bridged heterocyclyl, a monocyclic or bicyclic heteroaryl, phenyl, C3-8cycloalkyl(1-4C)alkyl, (4 to 7 membered monocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered fused bicyclic)heterocyclyl(1- 4C)alkyl, (5 to 9-membered spirocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered bridged)heterocyclyl(1-4C)alkyl, (monocyclic or bicyclic)heteroaryl(1-4C)alkyl, or phenyl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-4C)alkyl or (1-4C)haloalkyl in a substituent on the ZBgroup is optionally further substituted by one or more of halo, oxo, cyano, hydroxy, NH2or methyl; wherein if XBand YBare absent, then ZBis not hydrogen.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RBis a group of the formula: XB-YB-ZBwherein: XBis absent or [CH2]; YBis selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 to 9-membered fused bicyclic heterocyclyl, 5 to 9-membered spirocyclic heterocyclyl, 5 to 9-membered bridged heterocyclyl, a monocyclic or bicyclic heteroaryl, phenyl, C3-8cycloalkyl(1-4C)alkyl, (4 to 7 membered monocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered fused bicyclic)heterocyclyl(1- 4C)alkyl, (5 to 9-membered spirocyclic)heterocyclyl(1-4C)alkyl, (5 to 9-membered bridged)heterocyclyl(1-4C)alkyl; and wherein ZBis optionally substituted by one or more substituents independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; optionally wherein RBis a group of the formula:XB-YB-ZBwherein: XBis absent or [CH2]; YBis selected from -N(RY1)-, -C(O)-N(RY1)-, -N(RY1)-C(O)-, -O- or -S-, wherein RY1is selected from hydrogen or methyl; ZBis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, C3-8cycloalkyl(1-3C)alkyl or (4 to 7 membered monocyclic)heterocyclyl(1- 3C)alkyl; and wherein ZBis optionally substituted by one or more substituents selected from methyl, halo, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; further optionally wherein RBis a group with a formula selected from:, , , ,19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1ais hydrogen and R1bis methyl.

20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3a, R3b, R4aand R4bare each independently selected from hydrogen or halo; optionally R3a, R3b, R4aand R4bare each hydrogen.

21. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: i) R5is selected from hydrogen, halo or methoxy; optionally R5is hydrogen; and / or ii) R7is selected from hydrogen, halo, hydroxy or methoxy; optionally R7is hydrogen or hydroxy; further optionally R7is hydrogen.

22. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6is selected from hydrogen, hydroxy, methyl, halo, methoxy, fluoromethyl (e.g. CF3, CHF2, CHF2) or fluoromethoxy (e.g. OCF3, OCHF2, OCH2F); optionally wherein R6is selected from hydrogen, fluoro, chloro or fluoromethyl; further optionally wherein R6is selected from fluoro, chloro or trifluoromethyl.

23. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8is selected from hydrogen, hydroxy, methyl, halo, methoxy, fluoromethyl or fluoromethoxy; optionally wherein R8is selected from hydrogen, fluoro, chloro, bromo or trifluoromethyl; further optionally wherein R8is selected from hydrogen, fluoro or chloro; further optionally wherein R8is selected from hydrogen or chloro.

24. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ia), (Ib), (Ic), (IIa), (IIb) or (IIc) below:wherein Ring A, Ring B, R1a, R1b, R6, R8, RD2, RD4and RD7are as defined in any one of the preceding claims.

25. A compound selected from:(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(3-(pyridin-3-yl)piperidin-1- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)piperazin-2- yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)(6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)piperidin-3-yl)(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)pyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (3-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-azabicyclo[3.1.0]hexan-1-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)thiomorpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-methylmorpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6-chloro-8-fluoro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-8-fluoro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-difluoro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-6-fluoro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,4R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (methylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone;((3R,6S)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylpiperidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1-methylpiperazin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-((cyclopropylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- hydroxyethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methoxypyrrolidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((5R)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylpyrrolidin-3-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4RS)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((3RS,4SR)-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-methylpiperidin-3-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,5-difluoropiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-(cyclopropylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (ethylamino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-((cyclobutylmethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone;((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(piperidin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((R)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(6,8-dichloro-1,1-dimethyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyridin-3-yl)morpholin-2- yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3-yl)morpholin-2- yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-6,6-dimethyl-4-(pyridin-3- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyrimidin-5- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(imidazo[1,2-a]pyrazin-5- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-methyloxazolo[4,5- c]pyridin-7-yl)morpholin-2-yl)methanone; rac-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(pyridin-3- yl)thiomorpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-4-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;(4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)azepan-3-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (dimethylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- (methylamino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(thieno[2,3-c]pyridin-4- yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-7-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,3R)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-azaspiro[2.4]heptan-1-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-1,4-oxazepan-6-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(isothiazol-4- yl)morpholin-2-yl)methanone; ((R)-4-([1,2,4]triazolo[4,3-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-1-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3S)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1R,3R)-3-(2-aminooxazolo[4,5-c]pyridin-7-yl)cyclohexyl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(1-(pyridin-3-yl)pyrrolidin-3- yl)methanone; ((2RS,4SR)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(6-aminoimidazo[1,2-a]pyrazin-3-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2RS,4RS)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S)-4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(4-(6-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-2-oxabicyclo[2.1.1]hexan-1-yl)(6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4,6-dibromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-bromooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-4-methyloxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; N-(7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)acetamide; ((R)-4-(2-amino-4,6-dichlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-6-chlorooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-amino-7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridine-4-carbonitrile;((R)-4-(2-amino-4-iodooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((R)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2R,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)morpholine 4-oxide; 2-amino-7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridine 5-oxide; ((2R,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)morpholin-3-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((3- morpholinopropyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-amino-4-methoxyoxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-amino-7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-4(5H)-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(3-fluoroazetidin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(3,3- difluoroazetidin-1-yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(3- methoxyazetidin-1-yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone;((2R,6R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 5-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)morpholino)- 2,7-naphthyridin-1(2H)-one; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-fluoropiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6,6-dimethylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((R)- 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3-methoxypiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(thiazolo[4,5-c]pyridin-7- yl)morpholin-2-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-hydroxypiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[5,4-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-ethylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-7-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-oxa-7-azaspiro[2.5]octan-5-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(piperazin-1- yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone;((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2- (methylthio)thiazolo[5,4-c]pyridin-7-yl)morpholin-2-yl)methanone; ((R)-4-(2-(aminomethyl)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminobenzo[d]oxazol-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(pyrazolo[1,5- c]pyrimidin-3-yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylpiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(3,4- dimethoxyphenyl)morpholin-2-yl)methanone; ((2R,6R)-4-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-azabicyclo[2.2.2]octan-4-yl)(6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-fluoro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-8-fluoro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-amino-4-methoxybenzo[d]oxazol-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(5-methoxypyridin-3- yl)morpholin-2-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(hydroxymethyl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(1,7-naphthyridin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2,7-naphthyridin-4-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminothiazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)-2-oxa-5- azabicyclo[2.2.1]heptan-1-yl)((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)- yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(hydroxymethyl)morpholin-2-yl)((S)-8- chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(methoxymethyl)morpholin-2-yl)((S)-6,8- dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-(methoxymethyl)morpholin-2-yl)((S)-8- chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(3-amino-1,7-naphthyridin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((1S,4S)-5-(2-aminothiazolo[4,5-c]pyridin-7-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl)((S)- 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(2-aminooxazolo[4,5-c]pyridin-7-yl)-2-azabicyclo[2.2.1]heptan-4-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminothiazolo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)-5-methylmorpholin-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-amino-1,7-naphthyridin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; (2S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)morpholine-2-carboxylic acid; (2S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)-N,N-dimethylmorpholine-2-carboxamide; (2S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-((S)-6,8-dichloro-1-methyl-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)-N-methylmorpholine-2-carboxamide; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((2R)-4-(4-(morpholin-2- yl)pyridin-3-yl)morpholin-2-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,6-dihydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-6,8-dichloro-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-5,6-dihydro-2H-pyran-2-yl)((S)-8-chloro-1-methyl-6- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-3,6-dihydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S*,4S*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R*,4R*)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)tetrahydro-2H-pyran-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6-chloro-1-methyl-8- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)((R)-6-chloro-1-methyl-8- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (1-(2-aminooxazolo[4,5-c]pyridin-7-yl)-4-hydroxypiperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-amino-1-(2-aminooxazolo[4,5-c]pyridin-7-yl)piperidin-3-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2RS,4SR,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2- yl)((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4R*,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,4S,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4R,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2S,4S,6S)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone;((2R,4R,6R)-4-(2-aminooxazolo[4,5-c]pyridin-7-yl)-6-methyltetrahydro-2H-pyran-2-yl)((S)- 6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-6-methylmorpholin-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,6R)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-6-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-5-methylmorpholin-2-yl)((S)-6,8-dichloro- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((2R,5S)-4-(2-aminoimidazo[1,2-a]pyrazin-5-yl)-5-methylmorpholin-2-yl)((S)-8-chloro-1- methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 5-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)imidazo[1,2-a]pyrazine-2-carboxamide; 4-(2-((7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)amino)ethyl)piperazin-2-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- morpholinoethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(4,4- difluoropiperidin-1-yl)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2- thiomorpholinoethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-((2-(1,1- dioxidothiomorpholino)ethyl)amino)oxazolo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; 2-((7-((R)-2-((S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)morpholino)oxazolo[4,5-c]pyridin-2-yl)amino)-1-(piperazin-1-yl)ethan-1-one; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(imidazo[1,2-a]pyrazin-3- yl)morpholin-2-yl)methanone;((R)-4-(2-amino-1H-imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl- 3,4-dihydroisoquinolin-2(1H)-yl)methanone; ((R)-4-(1H-imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)((S)-6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(2-methyl-1H- imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(1-methyl-1H- imidazo[4,5-c]pyridin-7-yl)morpholin-2-yl)methanone; ((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(oxazolo[4,5-c]pyridin-7- yl)morpholin-2-yl)methanone; or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

27. A combination comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

28. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 26, or a combination according to claim 27, for use in therapy.

29. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 26, or a combination according to claim 27 for use in the treatment of: i) a proliferative condition; ii) cancer; optionally wherein the cancer is selected from solid organ cancer, lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma andlung squamous cell carcinoma), pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T- ALL); and chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia), breast cancer (including invasive breast carcinoma), bladder cancer (including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), intrahepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head and neck squamous cell carcinoma including squamous cell carcinoma of the oral tongue and nasopharyngeal carcinoma, esophageal squamous cell carcinoma), sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioma (including low grade glioma, diffuse glioma and glioblastoma multiforme / astrocytoma), adrenocortical carcinoma, melanoma, mature B-cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric adenocarcinoma, pheochromocytoma, endometrial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma), prostate carcinoma (including prostate adenocarcinoma), renal cancer (including clear cell renal cell carcinoma (ccRCC) and non-clear cell carcinoma), neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or mesothelioma; iii) leukaemia; optionally wherein the leukaemia is selected from: ● acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia; ● chronic myeloid leukaemia (CML) including chronic eosinophilic leukemia; ● acute lymphoblastic leukaemia (ALL) including precursor T-cell acute lymphoblastic leukemia (T-ALL); and ● chronic lymphoblastic leukaemia (CLL) including B-cell chronic lymphocytic leukemia;further optionally the leukaemia is selected from AML leukaemia or chronic myeloid leukaemia; iv) non-cancerous tumour growth, optionally ameloblastoma; or v) cardiac fibrosis.

30. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 26, or a combination according to claim 27 for use in the inhibition of METTL1 activity.

31. An intermediate compound selected from: (S)-6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline; (S)-8-chloro-1-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline; or 8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinoline); or a salt or solvate thereof.

32. A process for the synthesis of an intermediate of the formula (INT-A) the process comprising, reacting a compound of Formula (X-A)with a compound according to formula (Y-A):(Y-A) to form an intermediate accorindg to Formula (INT-A):(INT-A) 33. The process according to claim 32, wherein: a) compound (X-A) and (Y-A) are reacted in an appropriate solvent, preferably the solvent is an alcohol, for example ethanol, methanol, isopropanol or n-butanol; and / or b) compound (X-A) and (Y-A) are reacted at a temperature of from 60°C to 100°C, preferably from 70°C to 90°C.

34. A process for the synthesis of an intermediate of the the formula (INT-B), the process comprising step (c-1) shown below: (c-1) reacting a compound of Formula (X-B)(X-B) with a compound according to formula (Y-A):(Y-B) to form an intermediate of the formula (INT-B):(INT-B).

35. A process according to claim 34, wherein: a) compound (X-B) and (Y-B) are reacted under stereoselective hydrogenation conditions; b) compound (X-B) and (Y-B) are reacted in an appropriate solvent, preferably, the solvent is an alcohol, for example ethanol, methanol, isopropanol or n-butanol; and / or c) compound (X-B) and (Y-B) are reacted at a temperature of from 10°C to 40°C, for example from 15°C to 30°C; d) (X-B) and (Y-B) are reacted the presence of a catalyst, for example [Rh(η5- C5Me5)Cl2]2; e) (X-B) and (Y-B) are reacted in the presence of a Lewis base, for example DABCO (1,4-Diazabicyclo[2.2.2]octane); f) the compound (X-B) and (Y-B) are reacted in the presence of a hydrogen source, for example formic acid; and / or g) the method further comprises isolating intermediate (INT-B) as a suitable salt, for example a hydrochloric acid salt.

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