Inhibitory compounds

Abstract

The present invention relates to compounds of Formula (I) or (II), 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

1 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 such2 as cancer cells require elevated levels of protein 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 significantly3 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; 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 ameloblastoma and head and neck squamous cell carcinoma (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, which shows a summary of genomic alteration frequencies in the METTL1 gene, TCGA, PanCancer Atlas). 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 a4 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 myeloid leukemia (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 play 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 link5 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 or loss 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; Wang et al., 2023; Chen et al., 2024). METTL1 protein levels were found 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 therapy6 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; 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.,7 2019; Zhang et al., 2019). 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 modifications have been mapped in mRNAs by several orthogonal approaches, where they seem to enhance the translation of those mRNAs independent of their codon composition (Malbec et al., 2019; Zhang et al., 2019). 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] Therefore METTL1 inhibitors may provide a novel therapeutic approach to a range of proliferative diseases.

[0016] Thus, METTL1 inhibitors may also provide a novel therapeutic approach to enhance an anti-tumour response.

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(2024) ‘METTL1 mediated tRNA m7G modification promotes leukaemogenesis of AML via tRNA regulated translational control’, Experimental Hematology & Oncology, 13(1), p. 8. Available at: https: / / doi.org / 10.1186 / s40164-024- 00477-8. ^ Zhao, Z. et al. (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

[0018] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0019] 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.

[0020] 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.

[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 the treatment of a proliferative condition.

[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,12 for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[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 non-cancerous tumour growth (such as ameloblastoma).

[0024] In a particular embodiment, the cancer is a Haematologic cancer, such as any of those described herein.

[0025] In a particular embodiment, the cancer is a solid organ cancer, such as any of those described herein.

[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 medicament13 for use in the treatment of non-cancerous tumour growth. In a particular embodiment, the medicament is for use in ameloblastoma.

[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 for use 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.14

[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 amount of 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 non-cancerous tumour growth 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] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt, as defined herein.

[0047] 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.

[0048] 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.

[0049] 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

[0050] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0051] 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” of15 a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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,16 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.

[0057] 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.

[0058] 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-n- cycloalkyl” 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).

[0059] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

[0060] 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,17 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) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0061] 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 .

[0062] 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.18

[0063] 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.

[0064] 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.

[0065] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0066] 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;19 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0071] 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.

[0072] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically. Compounds of the invention

[0073] In one aspect, the present invention relates to compounds of the formula (I) or (II), or a pharmaceutically acceptable salt thereof:20RTis selected from hydrogen or fluoro; RVis selected from hydrogen or methyl; W is selected from CRWand N; X is selected from CRXand N; Y is selected from CRYand N; Z is selected from CRZand N; with the proviso that only one of W and X can be N, and only one of Y and Z can be N; wherein RWand RXare independently selected from hydrogen, halo, methyl, cyano or a group RA; with the proviso that when W is CRWand X is CRX, then at least one of RWand RXis selected from hydrogen, halo, methyl or cyano; wherein RAis a group of the formula: XA-YA-ZA21 wherein XAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, halo, ORX1, NRX1RX2, C3-6cycloalkyl or (1-2C)alkyl, wherein RX1and RX2are independently selected from hydrogen or methyl;or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; YAis absent or selected from -O-, -S-, -S(O)-, -S(O)2- -C(O)-, -C(O)O-, -OC(O)-, - CH(ORY1)-, -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; ZAis selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, C3- 12cycloalkyl, aryl (e.g. phenyl), heterocyclyl or heteroaryl; and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, heterocyclyl, heteroaryl, aryl, C3-8cycloalkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl, aryl(1-2C)alkyl, C3-8cycloalkyl(1-2C)- alkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2or S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl or aryl(1-2C)alkyl, in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, ORZ3, NRZ3RZ4, S(O)0-2RZ3or methyl; wherein RZ3and RZ4are each independently selected from hydrogen or (1- 2C)alkyl; RXN is selected from hydrogen, (1-6C)alkyl, heterocyclyl or C3-8cycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, (1-6C)haloalkyl, (1-6C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3, C(O)ORZ3, OC(O)RZ3, C(O)N(RZ3)RZ4, N(RZ3)C(O)RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or (1- 2C)alkyl; RYis selected from hydrogen, halo, NH2, cyano, or (1-2C)alkyl optionally substituted with NH2, hydroxy or cyano; RZis selected from hydrogen, halo, NH2, cyano, or (1-2C)alkyl optionally substituted with NH2, hydroxy or cyano,22 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; R6and R8are each independently selected from hydrogen, hydroxy, cyano, amino, (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, aryl or heteroaryl; wherein any (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, aryl or heteroaryl is optionally substituted with one or more of hydroxy, cyano, NH2, oxo, (1-4C)alkyl, halo, (1- 4C)haloalkyl or (1-4C)alkoxy; and Rpand Rqare independently selected from hydrogen, fluoro or methyl.

[0074] In another aspect, the present invention relates to compounds of the formula (I) or (II), or a pharmaceutically acceptable salt thereof:(II) RTis selected from hydrogen or fluoro;23 RVis selected from hydrogen or methyl; W is selected from CRWand N; X is selected from CRXand N; Y is selected from CRYand N; Z is selected from CRZand N; with the proviso that only one of W and X can be N, and only one of Y and Z can be N; wherein RWand RXare independently selected from hydrogen, halo, methyl, cyano or a group RA; with the proviso that when W is CRW and X is CRX, then at least one of RW and RX is selected from hydrogen, halo, methyl or cyano; wherein RAis a group of the formula: XA-YA-ZAwherein XAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, halo, ORX1, NRX1RX2, C3-6cycloalkyl or (1-2C)alkyl, wherein RX1and RX2are independently selected from hydrogen or methyl;or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(ORY1)-, -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; ZAis selected from hydrogen, (1-6C)alkyl, C3-12cycloalkyl, aryl (e.g. phenyl), heterocyclyl or heteroaryl; and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, heterocyclyl, heteroaryl, aryl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl, aryl(1-2C)alkyl, C3-8cycloalkyl, 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, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl or aryl(1- 2C)alkyl, in a substituent on the ZAgroup is optionally further substituted by one or24 more of halo, cyano, ORZ3, NRZ3RZ4or methyl; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl; RXNis selected from hydrogen, (1-6C)alkyl, heterocyclyl or C3-8cycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, (1-6C)haloalkyl, (1-6C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3, C(O)ORZ3, OC(O)RZ3, C(O)N(RZ3)RZ4, N(RZ3)C(O)RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or (1- 2C)alkyl; RY is selected from hydrogen, halo, NH2, cyano, or (1-2C)alkyl optionally substituted with NH2, hydroxy or cyano; RZ is selected from hydrogen, halo, NH2, cyano, or (1-2C)alkyl optionally substituted with NH2, hydroxy or cyano, R1a and R1b are independently selected from hydrogen, (1-2C)alkyl, halo, (1-2C)haloalkyl, with the proviso that at least one of R1a and R1b is not hydrogen; R3a, R3b, R4a and R4b are each independently selected from hydrogen, halo or methyl; R5 and R7 are each independently selected from hydrogen, halo, hydroxy, methyl or methoxy; R6 and R8 are each independently selected from hydrogen, hydroxy, cyano, amino, (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, aryl or heteroaryl; wherein any (1-4C)alkyl, heteroaryl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy or aryl is optionally substituted with one or more of hydroxy, cyano, NH2, oxo, (1-4C)alkyl, halo, (1- 4C)haloalkyl or (1-4C)alkoxy; and Rp and Rq are independently selected from hydrogen, fluoro or methyl.

[0075] Particular compounds of the invention include, for example, compounds of Formula (I) or (II), 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 (74) hereinafter:- (1) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula XA-YA-ZAwherein XAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, NRX1RX2, C3-25 6cycloalkyl or (1-2C)alkyl; or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(ORY1)-, -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; ZAis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, aryl (e.g. phenyl), heterocyclyl (including a monocyclic or bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system) or heteroaryl (including a 5- or 6- membered monocyclic heteroaryl or a 7 to 12 membered bicyclic heteroaryl); and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3- 8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl, aryl(1-2C)alkyl, 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, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl or phenyl(1- 2C)alkyl, in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2 or methyl. (2) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula XA-YA-ZAXAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, NRX1RX2, C3- 6cycloalkyl or (1-2C)alkyl; or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(ORY1)-, -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;26 ZAis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, phenyl, a 4 to 12-membered heterocyclyl (including a monocyclic heterocyclic ring system, a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system) or 5 to 12 membered heteroaryl (including a 5- or 6- membered monocyclic heteroaryl or a 7 to 12 membered bicyclic heteroaryl); and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, a 4 to 12-membered heterocyclyl, 5 to 12 membered heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, a 4 to 12-membered heterocyclyl(1-2C)alkyl, 5 to 12 membered heteroaryl(1-2C)alkyl, phenyl(1-2C)alkyl, 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, (1-6C)haloalkyl, 4 to 12-membered heterocyclyl, 5 to 12 membered heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, 4 to 12- membered heterocyclyl(1-2C)alkyl, 5 to 12 membered heteroaryl(1-2C)alkyl or phenyl(1-2C)alkyl in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2 or methyl. (3) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula XA-YA-ZAXAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, NRX1RX2, C3- 6cycloalkyl or (1-2C)alkyl; or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(ORY1)-, -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; ZAis selected from hydrogen, (1-6C)alkyl, C3-8cycloalkyl, phenyl, a 4 to 12-membered mono- or bicyclic heterocyclic ring system (including a monocyclic heterocyclic ring system, a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system) or 5 to 12 membered heteroaryl27 (including a 5- or 6- membered monocyclic heteroaryl or a 7 to 12 membered bicyclic heteroaryl); and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, a 4 to 12-membered mono or bicyclic heterocyclyl (including fused, bridged and spirocyclic heterocyclic ring systems), mono- or bicyclic heteroaryl, phenyl, C3-8cycloalkyl, 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, (1-6C)haloalkyl, 4 to 12-membered heterocyclyl, 5 to 12 membered heteroaryl or phenyl group in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, hydroxy, NH2 or methyl. (4) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula XA-YA-ZAwherein XAis absent or [CRXaH]n, wherein n is an integer selected from 1, 2 or 3, wherein RXais selected from hydrogen, NRX1RX2, C3-4cycloalkyl; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -C(O)-, -C(O)O-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZAis selected from hydrogen, (1-6C)alkyl, C3-6cycloalkyl, a 4 to 12-membered mono- or bicyclic heterocyclic ring system (including a 4 to 7 membered monocyclic heterocyclic ring system, a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system), a 5 to 12 membered mono- or bicyclic heteroaryl (including a 5- or 6- membered monocyclic heteroaryl or a 7 to 12 membered bicyclic heteroaryl); and wherein ZAis optionally substituted by one or more substituents selected from (1-2C)- alkyl, halo, (1-2C)haloalkyl, oxo, cyano, hydroxy, NRZ1RZ2, ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl. (5) RWand RXare selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula28 XA-YA-ZAwherein XAis absent or [CRXaH]n, wherein n is an integer selected from 1, 2 or 3, wherein RXais selected from hydrogen, NRX1RX2or C3-4cycloalkyl; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -C(O)-, -C(O)O-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZAis selected from hydrogen, (1-6C)alkyl, C3-6cycloalkyl, a 4 to 7 membered monocyclic heterocyclyl, a 5 to 10 membered fused, bridged or spirocyclic heterocycyl, a 5- or 6- membered monocyclic heteroaryl or a 7 to 10 membered bicyclic heteroaryl; and wherein ZAis optionally substituted by one or more substituents selected from (1-2C)- alkyl, halo, (1-2C)haloalkyl, oxo, cyano, hydroxy, NRZ1RZ2, ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl. (6) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula XA-YA-ZAwherein XAis absent or [CH2]n, wherein n is an integer selected from 1, 2 or 3; YAis absent or selected from -C(O)-, or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZAis selected from (1-6C)alkyl or a 5 or 6 membered monocyclic heterocyclyl; and wherein ZAis optionally substituted by one or more substituents selected from NRZ1RZ2, or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl. (7) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis selected from:36. (8) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group with a formula selected from: ,or . (9) RW and RX are independently selected from a group RAas defined herein.37 (10) If both of RWand RXare present, then one is as defined in any one of paragraphs (1) to (9) or paragraphs (67) to (74), and the other is selected from hydrogen, halo or methyl. (11) If both of RW and RX are present, then one is as defined in any one of paragraphs (1) to (9) or paragraphs (67) to (74), and the other is selected from hydrogen or fluoro. (12) W is CRW; and X is selected from CRX or N; wherein RX and RW are as defined herein. (13) W is CRW and X is CRX; wherein RX and RW are as defined herein. (14) W is CRW and X is N; wherein RW is as defined herein. (15) X is CRX; and W is selected from CRW or N; wherein RX and RW are as defined herein. (16) X is CRX and W is CRW; wherein RX and RW are as defined herein. (17) X is CRX and W is N; wherein RX is as defined herein. (18) RXN is selected from hydrogen, (1-4C)alkyl, monocyclic heterocyclyl or C3-6cycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, (1-4C)haloalkyl, (1-4C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3, C(O)ORZ3, OC(O)RZ3, C(O)N(RZ3)RZ4, N(RZ3)C(O)RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl. (19) RXNis selected from hydrogen or (1-4C)alkyl, monocyclic heterocyclyl or C3-6cycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, (1-2C)haloalkyl, (1-2C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3or C(O)ORZ3; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl. (20) RXNis selected from hydrogen or (1-4C)alkyl optionally substituted by one or more substituents selected from halo, (1-2C)haloalkyl, (1-2C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3or C(O)ORZ3; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl.38 (21) RXNis selected from hydrogen or (1-4C)alkyl optionally substituted by one or more substituents selected from halo, cyano, NRZ3RZ4or ORZ3, wherein RZ3is selected from hydrogen or methyl. (2 (2. (23) Y is CRY. (24) RYis selected from hydrogen, halo, NH2, cyano or methyl optionally substituted with NH2, hydroxy or cyano. (25) RYis selected from hydrogen, halo, NH2, cyano, CH2NH2or CH2OH. (26) RYis selected from hydrogen, halo, NH2or cyano. (27) RYis hydrogen. (28) Z is CRZ. (29) RZis selected from hydrogen, halo, NH2, cyano, or methyl optionally substituted with NH2, hydroxy or cyano. (30) RZis selected from hydrogen, halo, NH2, cyano or CH2OH. (31) RZis selected from hydrogen or halo. (32) RZ is selected from hydrogen or fluoro. (33) RZ is selected from fluoro. (34) RTis hydrogen. (35) RV is hydrogen. (36) Rp and Rq are each hydrogen. (37) R1a and R1b are independently selected from hydrogen, (1-2C)alkyl, halo, (1- 2C)haloalkyl, with the proviso that at least one of R1a and R1b is not hydrogen; (38) R1a is hydrogen and R1b is selected from (1-2C)alkyl and (1-2C)haloalkyl.39 (39) R1ais hydrogen and R1bis methyl. (40) R1bis hydrogen and R1ais selected from (1-2C)alkyl and (1-2C)haloalkyl. (41) R1bis hydrogen and R1ais methyl. (42) R3a, R3b, R4aand R4bare each independently selected from hydrogen or halo. (43) R3a, R3b, R4a and R4b are each hydrogen. (44) R5is selected from hydrogen, halo or methoxy. (45) R5is hydrogen or halo. (46) R5 is hydrogen. (47) R6 is selected from hydrogen, hydroxy, cyano, amino, (1-2C)alkyl, halo, (1- 2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, 5- or 6 membered heteroaryl or phenyl; wherein any (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, 5- or 6 membered heteroaryl or phenyl is optionally substituted with one or more substituents selected from hydroxy, cyano, amino, oxo, methyl, halo, halomethyl or methoxy. (48) R6 is selected from hydrogen, hydroxy, cyano, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)alkoxy, 5- or 6 membered heteroaryl or phenyl; wherein any wherein any (1- 2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, 5- or 6 membered heteroaryl or phenyl is optionally substituted with one or more substituents selected from hydroxy, cyano, amino or halo. (49) R6 is selected from hydrogen, halo, halomethyl, methoxy, 5- or 6 membered heteroaryl or phenyl. (50) R6 is selected from hydrogen, hydroxy, cyano, amino, methyl, fluoromethyl (e.g. CF3, CHF2 or CH2F), halo (e.g. F, Cl or Br), methoxy or fluoromethoxy (e.g. OCF3, OCHF2 or OCH2F). (51) R6 is selected from hydrogen, hydroxy, methyl, fluoro, chloro, bromo, methoxy, trifluoromethyl, OCF3, OCHF2 or OCH2F. (52) R6 is selected from hydrogen, methyl, fluoro, chloro or bromo. (53) R6is selected from hydrogen, methyl, trifluoromethyl, fluoro, chloro or bromo. (54) R6is selected from chloro or trifluoromethyl. (55) R6is selected from fluoro or chloro. (56) R7is selected from hydrogen, halo, hydroxy or methoxy. (57) R7is selected from hydrogen or hydroxy, (58) R7is hydrogen. (59) R8is selected from hydrogen, hydroxy, cyano, amino, methyl, halo, halomethyl, methoxy, 5- or 6 membered heteroaryl and phenyl; wherein any methyl, 5- or 6 membered heteroaryl and phenyl is optionally substituted with one or more of hydroxy, cyano, amino, oxo, methyl, halo, halomethyl or methoxy.40 (60) R8is selected from hydrogen, hydroxy, methyl, halo, trifluoromethyl, methoxy, 5- or 6- membered heteroaryl and phenyl; wherein any methyl, 5- or 6 membered heteroaryl and phenyl is optionally substituted with one or more of halo, hydroxy, cyano or amino. (61) R8 is selected from hydrogen, hydroxy, methyl, fluoro, chloro, bromo, methoxy, fluoromethyl or fluoromethoxy. (62) R8is selected from hydrogen, methyl, fluoro, chloro, bromo or methoxy. (63) R8 is selected from hydrogen, methyl, fluoro, chloro or methoxy. (64) R8 is selected from hydrogen, fluoro or chloro. (65) R8 is selected from fluoro or chloro. (66) R8 is selected from hydrogen or chloro. (67) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZAwherein XAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, NRX1RX2, C3- 6cycloalkyl or (1-2C)alkyl; or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(ORY1)-, -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; ZAis selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, 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) or heteroaryl (including a monocyclic or bicyclic heteroaryl ring system); and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl, aryl(1-2C)alkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2and S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl;41 and any (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alky; or phenyl(1-2C)alkyl, in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, ORZ3, NRZ3RZ4or methyl; wherein RZ3and RZ4are each independently selected from hydrogen or (1- 2C)alkyl. (68) RWand RXare independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZAwherein XAis absent or [CRXaH]n, wherein n is an integer selected from 1, 2 or 3, wherein RXais selected from hydrogen, NRX1RX2or C3-4cycloalkyl; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZAis selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, C3-6cycloalkyl, 4 to 12- membered mono- or bicyclic heterocyclyl (e.g. a fused, bridged or spirocyclic heterocyclic ring system) or mono- or bicyclic heteroaryl; and wherein ZAis optionally substituted by one or more substituents selected from (1-4C)- alkyl, halo, (1-4C)haloalkyl, 4- to 6-membered heterocyclyl, C3-6cycloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)N(RZ1)RZ2or S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any alkyl, haloalkyl, 4- to 6-membered heterocyclyl or C3-6cycloalkyl in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, ORZ3, NRZ3RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or methyl. (69) RWand RXare independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZAwherein XAis absent or [CH2]n, wherein n is an integer selected from 1 or 2;42 YAis absent or selected from -O-, -C(O)-, -C(O)O-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZAis selected from hydrogen, (1-4C)alkyl, (2-4C)alkenyl, C3-6cycloalkyl, 4 to 10- membered mono- or bicyclic heterocyclyl (e.g. a fused, bridged or spirocyclic heterocyclic ring system) or mono- or bicyclic heteroaryl; and wherein ZAis optionally substituted by one or more substituents selected from (1-4C)- alkyl, halo, (1-4C)haloalkyl, 4- to 6-membered heterocyclyl, C3-6cycloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)N(RZ1)RZ2or S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; and any alkyl, haloalkyl, 4- to 6-membered heterocyclyl or C3-6cycloalkyl in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, hydroxy, methoxy or NH2. (70) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZAwherein XAis absent or [CH2]n, wherein n is an integer selected from 1, 2 or 3; YAis absent or selected from -C(O)-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is independently selected from hydrogen or methyl; ZAis selected from hydrogen, (1-6C)alkyl, C3-6cycloalkyl, or a 4- to 6- membered monocyclic heterocyclyl; and wherein ZAis optionally substituted by one or more substituents selected from (1-4C)- alkyl, halo, (1-2C)haloalkyl, 4- to 6-membered monocyclic heterocyclyl, C3-6cycloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; wherein any alkyl, haloalkyl, 4- to 6-membered heterocyclyl or C3-6cycloalkyl in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, hydroxy, methoxy or NH2. (71) RWand RXare independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZA43 wherein XAis absent or [CH2]n, wherein n is an integer selected from 1, 2 or 3; YAis absent or selected from -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is independently selected from hydrogen or methyl; ZAis selected from hydrogen, (1-4C)alkyl, C3-6cycloalkyl or 4- to 6- membered monocyclic heterocyclyl; and wherein ZAis optionally substituted by one or more substituents selected from NRZ1RZ2, or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl. (72) RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group with a formula selected from: , ,, , ,53 nd(73) RW and RX are independently selected from hydrogen or a group RA; wherein RAis a group with a formula selected from: ,or ; wherein at least one of RW and RX is hydrogen. (74) RW and RX are hydrogen.

[0076] Suitably, RW and RX are as defined in any one of paragraphs (1) to (9) and (67) to (74). More suitably, RW and RX are as defined in any one of paragraphs (3) to (6), (7) to (9), (69) to (71) and (72) to (74). Even more suitably, RW and RX are as defined in any one of paragraphs (6), (7), (8), (9), (70), (71), (72), (73) or (74).54

[0077] Suitably, RWand RXare as defined in any one of paragraphs (1) to (9). More suitably, RWand RXare as defined in any one of paragraphs (3) to (6) or (7) to (9). Most suitably, RWand RXare as defined in any one of paragraphs (6), (7), (8) or (9).

[0078] Suitably, RWis as defined in any one of paragraphs (67) to (74). More suitably, RWis as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74). More suitably, RW is as defined in any one of paragraphs (71), (72), (73) or (74). Most suitably, RWis as defined in any one of paragraphs (73) or (74).

[0079] Suitably, RX is as defined in any one of paragraphs (67) to (74). More suitably, RX is as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74). More suitably, RX is as defined in any one of paragraphs (71), (72), (73) or (74). Most suitably, RX is as defined in any one of paragraphs (73) or (74).

[0080] Suitably, if both of RW and RX are present, then they are as defined in paragraph (10) or (11). More suitably, if both of RW and RX are present, then they are as defined in paragraph (11). Most suitably, if both of RW and RX are present, then one of RW and RX is hydrogen, and the other is as defined in any one of paragraphs (1) to (9) or paragraphs (67) to (74).Suitably, RAis as defined in any one of paragraphs (1) to (8). More suitably, RAis as defined in any one of paragraphs (3) to (8). Most suitably, RAis as defined in any one of paragraphs (6), (7) or (8).

[0081] Suitably, RAis as defined in any one of paragraphs (1) to (8) and (67) to (73). More suitably, RAis as defined in any one of paragraphs (3) to (8) or (69) to (73). Most suitably, RAis as defined in any one of paragraphs (6), (7), (8), (70), (71), (72) or (73).

[0082] Suitably, RAis as defined in any one of paragraphs (67) to (73). More suitably, RAis as defined in any one of paragraphs (69), (70), (71), (72) or (73). Most suitably, RAis as defined in any one of paragraphs (71), (72) or (73).

[0083] Suitably W and X are as defined in any one of paragraphs (12) to (17).

[0084] Suitably, W is CRW, wherein RW is as defined in any one of paragraphs (1) to (9). and X is selected from CRX or N, wherein RX is selected from hydrogen, halo, methyl or cyano. More suitably, W is CRW, wherein RWis a group RAas defined in any one of paragraphs (3) to (6) or (7) to (9); and X is selected from CRXor N, wherein RXis selected from hydrogen or fluoro. Most suitably, W is CRW, wherein RWis a group RAas defined in any one of paragraphs (6), (7), (8) or (9); and X is selected from CH or N.

[0085] Suitably, X is CRX, wherein RXis as defined in any one of paragraphs (1) to (9); and W is selected from CRWor N, wherein RWis selected from hydrogen, halo, methyl or cyano. More suitably, X is CRX, wherein RXis a group RAas defined in any one of paragraphs (3) to (6) or (7) to (9); and W is selected from CRWor N, wherein RWis selected from hydrogen or fluoro. Most suitably, X is CRX, wherein RXis as defined in any one of paragraphs (6), (7), (8) or (9); and W is selected from CH or N.55

[0086] Suitably, W is CRW, wherein RWis as defined in any one of paragraphs (67) to (74). and X is selected from CRXor N, wherein RXis selected from hydrogen, halo, methyl or cyano. More suitably, W is CRW, wherein RWis hydrogen or a group RAas defined in any one of paragraphs (69), (70), (71), (72) or (73); and X is selected from CRXor N, wherein RXis selected from hydrogen or fluoro. Most suitably, W is CRW, wherein RW is hydrogen or a group RAas defined in any one of paragraphs (71), (72) or (73); and X is selected from CH or N.

[0087] Suitably, X is CRX, wherein RX is as defined in any one of paragraphs (67) to (74); and W is selected from CRW or N, wherein RW is selected from hydrogen, halo, methyl or cyano. More suitably, X is CRX, wherein RX is hydrogen or a group RAas defined in any one of paragraphs (69), (70), (71), (72) or (73); and W is selected from CRW or N, wherein RW is selected from hydrogen or fluoro. Most suitably, X is CRX, wherein RX is hydrogen or a group RAas defined in any one of paragraphs (71), (72) or (73); and W is selected from CH or N.

[0088] Suitably, RXN is as defined in any one of paragraphs (18) to (22) and (22a). More suitably, RXN is as defined in any one of paragraphs (20) to (22) and (22a). Most suitably, RXN is as defined in paragraph (21) or (22). Suitably RXN is as defined in paragraph (22a).

[0089] Suitably, Y is as defined in paragraph (23).

[0090] Suitably, RY is as defined in any one of paragraphs (24) to (27). More suitably, RY is as defined in paragraph (26) or (27). Most suitably, RY is as defined in paragraph (27).

[0091] Suitably, Z is as defined in any one of paragraphs (28).

[0092] Suitably, RZ is as defined in any one of paragraphs (29) to (33). More suitably, RZ is as defined in paragraph (31), (32) or (33). Most suitably, RZ is as defined in paragraph (33).

[0093] Suitably, RT is as defined in paragraph (34).

[0094] Suitably, RV is as defined in paragraph (35).

[0095] Suitably, Rp and Rq are as defined in paragraph (36).

[0096] Suitably, R1a and R1b are as defined in any one of paragraphs (37) to (41). More suitably, R1aand R1bare as defined in any one of paragraphs (38) to (41). Most suitably, R1aand R1bare as defined in paragraph (39) or (41).

[0097] Suitably, R3a, R3b, R4aand R4bare as defined in paragraph (42) or (43). Most suitably, R3a, R3b, R4aand R4bare as defined in paragraph (43).

[0098] Suitably, R5is as defined in any one of paragraphs (44) to (46). More suitably, R5is as defined in paragraph (45) or (46). Most suitably, R5is as defined in paragraph (46).

[0099] Suitably, R6is as defined in any one of paragraphs (47), (48), (49), (52) or (55). More suitably, R6is as defined in any one of paragraphs (49), (52) or (55). Most suitably, R6is as defined in paragraph (52) or (55).56

[0100] Suitably, R6is as defined in any one of paragraphs (47) to (55). More suitably, R6is as defined in any one of paragraphs (51) to (54). Most suitably, R6is as defined in paragraph (53) or (54).

[0101] Suitably, R7is as defined in any one of paragraphs (56), (57) or (58). Suitably, R7 is as defined in paragraph (56) or (58). More suitably, R7 is as defined in paragraph (58).

[0102] Suitably, R8is as defined in any one of paragraphs (59), (60), (63), (64) or (65). More suitably, R8 is as defined in any one of paragraphs (63), (64) or (65). Most suitably, R8 is as defined in paragraph (64) or (65).

[0103] Suitably, R8 is as defined in any one of paragraphs (61) to (66). More suitably, R8 is as defined in any one of paragraphs (62), (64) or (66). Most suitably, R8 is as defined in paragraph (64) or (66).

[0104] In an embodiment, the compound is of Formula (Ia) below:wherein: RW, R1a, R1b, R6, R8, and Rz are each as defined herein; and X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, halo, methyl or cyano; or a pharmaceutically acceptable salt thereof.

[0105] In an embodiment of the compounds of Formula (Ia): RW is as defined in any one of paragraphs (1) to (9); X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl, e.g. hydrogen or fluoro; R1a, R1b, R6, R8, and Rz are as defined herein.

[0106] In an embodiment of the compounds of Formula (Ia): RW is defined in any one of paragraphs (3) to (6) or (7) to (9); X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl;57 R1aand R1b, are as defined herein. R6is as defined in any one of paragraphs (47), (48), (49), (52) or (55); R8is as defined in any one of paragraphs (59), (60), (63), (64) or (65); and Rzis as defined in any one of paragraphs (29) to (33).

[0107] In an embodiment of the compounds of Formula (Ia): RWis as defined in any one of paragraphs (6), (7), (8) or (9) X is C-RXa1or N; wherein RXa1is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in any one of paragraphs (38) to (41); R6 is as defined in any one of paragraphs (49), (52) or (55); R8 is as defined in any one of paragraphs (63), (64) or (65); and Rz is as defined in any one of paragraphs (31) to (33).

[0108] In an embodiment of the compounds of Formula (Ia): RW is as defined in any one of paragraphs (6), (7), (8) or (9) X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (52) or (55); R8 is as defined in paragraph (64) or (65); and Rz is as defined in paragraph (33).

[0109] In an embodiment of the compounds of Formula (Ia): RW is as defined in any one of paragraphs (67) to (74); X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl; W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl, e.g. hydrogen or fluoro; R1a, R1b, R6, R8, and Rz are as defined herein.

[0110] In an embodiment of the compounds of Formula (Ia): RW is as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74); X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl; W is C-RWa1or N; wherein RWa1is selected from hydrogen, fluoro or methyl; R1aand R1b, are as defined herein. R6is as defined in any one of paragraphs (47) to (55); R8is as defined in any one of paragraphs (61) to (66); and Rzis as defined in any one of paragraphs (29) to (33).

[0111] In an embodiment of the compounds of Formula (Ia):58 RWis as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74); X is C-RXa1or N; wherein RXa1is selected from hydrogen, fluoro or methyl; W is C-RWa1or N; wherein RWa1is selected from hydrogen, fluoro or methyl; R1aand R1bare as defined in any one of paragraphs (38) to (41); R6 is as defined in any one of paragraphs (51) to (54); R8is as defined in any one of paragraphs (62), (64) or (66); and Rzis as defined in any one of paragraphs (31) to (33).

[0112] In an embodiment of the compounds of Formula (Ia): RW is as defined in paragraph (73) or (74); X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl; W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (53) or (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0113] In an embodiment of the compounds of Formula (Ia): RW is as defined in paragraph (73) or (74); X is C-RXa1 or N; wherein RXa1 is selected from hydrogen, fluoro or methyl; W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0114] In an embodiment, the compound is of Formula (Ib) below:(Ib) wherein: RX, RXN, R1a, R1b, R6, R8, and Rz are each as defined herein; and59 W is C-RWa1or N; wherein RWa1is selected from hydrogen, halo, methyl or cyano; or a pharmaceutically acceptable salt thereof.

[0115] In an embodiment of the compounds of Formula (Ib): RXis as defined in any one of paragraphs (1) to (9); W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl, e.g. hydrogen or fluoro; R1a, R1b, R6, R8, and Rzare as defined herein.

[0116] In an embodiment of the compounds of Formula (Ib): RX is as defined in any one of paragraphs (3) to (6) or (7) to (9); W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b, are as defined herein. R6 is as defined in any one of paragraphs (47), (48), (49), (52) or (55); R8 is as defined in any one of paragraphs (59), (60), (63), (64) or (65); and Rz is as defined in any one of paragraphs (29) to (33).

[0117] In an embodiment of the compounds of Formula (Ib): RX is as defined in any one of paragraphs (6), (7), (8) or (9) W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in any one of paragraphs (38) to (41); R6 is as defined in any one of paragraphs (49), (52) or (55); R8 is as defined in any one of paragraphs (63), (64) or (65); and Rz is as defined in any one of paragraphs (31) to (33).

[0118] In an embodiment of the compounds of Formula (Ib): RX is as defined in any one of paragraphs (6), (7), (8) or (9) W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (52) or (55); R8 is as defined in paragraph (64) or (65); and Rzis as defined in paragraph (33).

[0119] In an embodiment of the compounds of Formula (Ib): RXis as defined in any one of paragraphs (67) to (74); W is C-RWa1or N; wherein RWa1is selected from hydrogen, fluoro or methyl; R1a, R1b, R6, R8, and Rzare as defined herein.

[0120] In an embodiment of the compounds of Formula (Ib):60 RXis as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74); W is C-RWa1or N; wherein RWa1is selected from hydrogen, fluoro or methyl; R1aand R1b, are as defined herein. R6is as defined in any one of paragraphs (47) to (55); R8 is as defined in any one of paragraphs (61) to (66); and Rzis as defined in any one of paragraphs (29) to (33).

[0121] In an embodiment of the compounds of Formula (Ib): RX is as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74); W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in any one of paragraphs (38) to (41); R6 is as defined in any one of paragraphs (51) to (54); R8 is as defined in any one of paragraphs (62), (64) or (66); and Rz is as defined in any one of paragraphs (31) to (33).

[0122] In an embodiment of the compounds of Formula (Ib): RX is as defined in any one of paragraphs (72), (73) or (74); W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (53) or (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0123] In an embodiment of the compounds of Formula (Ib): RX is as defined in paragraph (73) or (74); W is C-RWa1 or N; wherein RWa1 is selected from hydrogen, fluoro or methyl; R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0124] In an embodiment the compound is of Formula (IIa) below:61 (IIa) wherein RXN, R1a, R1b, R6, R8, and Rzare each as defined herein, or a pharmaceutically acceptable salt thereof.

[0125] In an embodiment of the compounds of Formula (IIa): RXNis as defined in any one of paragraphs (18) to (22) and (22a); R1a, R1b, R6, R8, and Rz are as defined herein.

[0126] In an embodiment of the compounds of Formula (IIa): RXN is as defined in any one of paragraphs (20) to (22) and (22a); R1a and R1b, are as defined herein. R6 is as defined in any one of paragraphs (47), (48), (49), (52) or (55); R8 is as defined in any one of paragraphs (59), (60), (63), (64) or (65); and Rz is as defined in any one of paragraphs (29) to (33).

[0127] In an embodiment of the compounds of Formula (IIa): RXN is as defined in paragraph (22) or (22a); R1a and R1b are as defined in any one of paragraphs (38) to (41); R6 is as defined in any one of paragraphs (49), (52) or (55); R8 is as defined in any one of paragraphs (63), (64) or (65); and Rz is as defined in any one of paragraphs (31) to (33).

[0128] In an embodiment of the compounds of Formula (IIa): RXN is as defined in paragraph (22) or (22a); R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (52) or (55); R8 is as defined in paragraph (64 ) or (65); and Rz is as defined in paragraph (33).

[0129] In an embodiment of the compounds of Formula (IIa): RXN is as defined in any one of paragraphs (18) to (22) and (22a); R1a, R1b, R6, R8, and Rz are as defined herein.

[0130] In an embodiment of the compounds of Formula (IIa): RXNis as defined in any one of paragraphs (20) to (22) and (22a); R1aand R1b, are as defined herein. R6is as defined in any one of paragraphs (47) to (55);62 R8is as defined in any one of paragraphs (61) to (66); and Rzis as defined in any one of paragraphs (29) to (33).

[0131] In an embodiment of the compounds of Formula (IIa): RXNis as defined in paragraph (22); R1a and R1b are as defined in any one of paragraphs (38) to (41); R6is as defined in any one of paragraphs (51) to (54); R8is as defined in any one of paragraphs (62), (64) or (66); and Rz is as defined in any one of paragraphs (31) to (33).

[0132] In an embodiment of the compounds of Formula (IIa): RXN is as defined in paragraph (22); R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (53) or (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0133] In an embodiment of the compounds of Formula (IIa): RXN is as defined in paragraph (22); R1a and R1b are as defined in paragraph (39) or (41); R6 is as defined in paragraph (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0134] Suitably, the compound is of Formula (Ia) or (Ib) as defined herein; or a pharmaceutically acceptable salt thereof.

[0135] In an embodiment, the compound is of Formula (Ic) or (Id) below:(Ic)63wherein RW, R6, R8, and Rzare as defined herein, or a pharmaceutically acceptable salt thereof.

[0136] In an embodiment, the compound is of Formula (Ie) or (If) below:(If) wherein RX, R6, R8, and Rzare as defined herein, or a pharmaceutically acceptable salt thereof.

[0137] Suitably, the compound is of Formula (Ic) or (Id) as defined herein.

[0138] In an embodiment, the compound is of Formula (Ig) or (Ih) below:64wherein RW, R6, R8, and Rzare as defined herein, or a pharmaceutically acceptable salt thereof.

[0139] In an embodiment, the compound is of Formula (Ij) or (Ik) below:(Ij)65wherein RX,R6, R8, and Rzare as defined herein, or a pharmaceutically acceptable salt thereof.

[0140] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RWis as defined in any one of paragraphs (1) to (9); R6, R8, and Rzare as defined herein.

[0141] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RWis as defined in any one of paragraphs (3) to (6) or (7) to (9); R6is as defined in any one of paragraphs (47), (48), (49), (52) or (55); R8is as defined in any one of paragraphs (59), (60), (63), (64) or (65); and Rzis as defined in any one of paragraphs (29) to (33).

[0142] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RW is as defined in any one of paragraphs (6), (7), (8) or (9) R6 is as defined in any one of paragraphs (49), (52) or (55); R8 is as defined in any one of paragraphs (63), (64) or (65); and Rz is as defined in any one of paragraphs (31) to (33).

[0143] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RW is as defined paragraph (8) or (9) R6 is as defined in paragraph (52) or (55); R8 is as defined in paragraph (64) or (65); and Rz is as defined in paragraph (33).

[0144] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RW is as defined in any one of paragraphs (67) to (74); R6, R8, and Rz are as defined herein.

[0145] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih):66 RWis as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74); R6is as defined in any one of paragraphs (47) to (55); R8is as defined in any one of paragraphs (61) to (66); and Rzis as defined in any one of paragraphs (29) to (33).

[0146] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RWis as defined in any one of paragraphs (72), (73) or (74); R6is as defined in any one of paragraphs (51) to (54); R8 is as defined in any one of paragraphs (62), (64) or (66); and Rz is as defined in any one of paragraphs (31) to (33).

[0147] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RW is as defined in paragraph (73) or (74); R6 is as defined in paragraph (53) or (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0148] In an embodiment of the compounds of Formula (Ic), (Id), (Ig) or (Ih): RW is as defined in paragraph (74) R6 is as defined in paragraph (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0149] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RX is as defined in any one of paragraphs (1) to (9); R6, R8, and Rz are as defined herein.

[0150] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RX is as defined in any one of paragraphs (3) to (6) or (7) to (9); R6 is as defined in any one of paragraphs (47), (48), (49), (52) or (55); R8 is as defined in any one of paragraphs (59), (60), (63), (64) or (65); and Rz is as defined in any one of paragraphs (29) to (33).

[0151] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RXis as defined in any one of paragraphs (6), (7), (8) or (9) R6is as defined in any one of paragraphs (49), (52) or (55); R8is as defined in any one of paragraphs (63), (64) or (65); and Rzis as defined in any one of paragraphs (31) to (33).

[0152] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik):67 RXis as defined paragraph (8) or (9) R6is as defined in paragraph (52) or (55); R8is as defined in paragraph (64) or (65); and Rzis as defined in paragraph (33).

[0153] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RXis as defined in any one of paragraphs (67) to (74); R6, R8, and Rzare as defined herein.

[0154] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RX is as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74); R6 is as defined in any one of paragraphs (47) to (55); R8 is as defined in any one of paragraphs (61) to (66); and Rz is as defined in any one of paragraphs (29) to (33).

[0155] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RX is as defined in any one of paragraphs (69), (70), (71), (72), (73) or (74) R6 is as defined in any one of paragraphs (51) to (54); R8 is as defined in any one of paragraphs (62), (64) or (66); and Rz is as defined in any one of paragraphs (31) to (33).

[0156] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RX is as defined in paragraph (72), (73) or (74); R6 is as defined in paragraph (53) or (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0157] In an embodiment of the compounds of Formula (Ie), (If), (Ij) or (Ik): RX is as defined in paragraph (73) or (74); R6 is as defined in paragraph (54); R8 is as defined in paragraph (64) or (66); and Rz is as defined in paragraph (33).

[0158] In an embodiment, the compound is of Formula (IIb) below:68wherein RXNR6, R8, and Rzare as defined herein, or a pharmaceutically acceptable salt thereof.

[0159] In an embodiment, the compound is of Formula (IIc) below:wherein RXNR6, R8, and Rzare as defined herein, or a pharmaceutically acceptable salt thereof.

[0160] In an embodiment of the compounds of Formula (IIb) or (IIc): RXNis as defined in any one of paragraphs (18) to (22) and (22a); R6, R8and Rzare as defined herein.

[0161] In an embodiment of the compounds of Formula (IIb) or (IIc): RXNis as defined in any one of paragraphs (20) to (22) and (22a); R6is as defined in any one of paragraphs (47), (48), (49), (52) or (55); R8is as defined in any one of paragraphs (59), (60), (63), (64) or (65); and Rzis as defined in any one of paragraphs (29) to (33).

[0162] In an embodiment of the compounds of Formula (IIb) or (IIc): RXN is as defined in paragraph (22) or (22a); R6 is as defined in any one of paragraphs (49), (52) or (55);69 R8is as defined in any one of paragraphs (63), (64) or (65); and Rzis as defined in any one of paragraphs (31) to (33).

[0163] In an embodiment of the compounds of Formula (IIb) or (IIc): RXNis as defined in paragraph (22) or (22a); R6 is as defined in paragraph (55); R8is as defined in paragraph (66); and Rzis as defined in paragraph (33).

[0164] In an embodiment of the compounds of Formula (IIb) or (IIc): RXN is as defined in paragraph (22) or (22a); R6 is as defined in paragraph (55); R8 is as defined in paragraph (64); and Rz is as defined in paragraph (33).

[0165] In an embodiment of the compounds of Formula (IIb) or (IIc): RXN is as defined in any one of paragraphs (18) to (22); R6, R8 and Rz are as defined herein.

[0166] In an embodiment of the compounds of Formula (IIb) or (IIc): RXN is as defined in any one of paragraphs (20) to (22); R6 is as defined in any one of paragraphs (47) to (55); R8 is as defined in any one of paragraphs (61) to (66); and Rz is as defined in any one of paragraphs (29) to (33).

[0167] In an embodiment of the compounds of Formula (IIb) or (IIc): RXN is as defined in paragraph (22); R6 is as defined in any one of paragraphs (51) to (54); R8 is as defined in any one of paragraphs (62), (64) or (66); and Rz is as defined in any one of paragraphs (31) to (33).

[0168] In an embodiment of the compounds of Formula (IIb) or (IIc): RXN is as defined in paragraph (22); R6is as defined in paragraph (53) or (54); R8is as defined in paragraph (64) or (66); and Rzis as defined in paragraph (33).

[0169] In an embodiment of the compounds of Formula (IIb) or (IIc): RXNis as defined in paragraph (22);70 R6is as defined in paragraph (54); R8is as defined in paragraph (64) or (66); and Rzis as defined in paragraph (33).

[0170] 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.

[0171] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0172] 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)].

[0173] Suitably, an aryl group is phenyl.

[0174] 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-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1-one; 6-[[2-oxo-2-(1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]amino]-2H-isoquinolin-1- one; 7-fluoro-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 8-fluoro-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 6-[[2-(1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1-one; 6-[[2-(8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 6-[[2-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one;71 6-[[2-(6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- 2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-(1,1,6-trimethyl-3,4-dihydroisoquinolin-2-yl)ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-[(1S)-1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 7-[[2-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro- 3H-quinazolin-4-one; 6-fluoro-7-[[2-oxo-2-[(1S)-8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-quinazolin-4-one 6-[[2-oxo-2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]-2H- isoquinolin-1-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 7-[[2-(8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6- fluoro-3H-quinazolin-4-one; 7-[[2-(6-chloro-8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6- fluoro-3H-quinazolin-4-one; 6-fluoro-7-[[2-(8-fluoro-1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 6-fluoro-7-{[2-(6-fluoro-1,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]amino}- 3,4-dihydroquinazolin-4-one; 6-[[2-(5-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 7-fluoro-6-[[2-(7-hydroxy-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-2H-isoquinolin-1-one;72 7-fluoro-6-[[2-(7-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 7-fluoro-6-[[2-(7-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-(8-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 3-methyl-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 2-amino-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-quinazolin-4- one; 6-[[2-[1-(difluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 2-methyl-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-quinazolin- 4-one; 3-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7H-pyrido[2,3- d]pyridazin-8-one; 7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-pyrido[3,2- d]pyrimidin-4-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-4,7-difluoro- 2H-isoquinolin-1-one; 7-[[2-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- methyl-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- methyl-3H-quinazolin-4-one; (R)- 7‐({2‐[8‐chloro‐6‐fluoro‐1‐methyl‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl]‐2‐oxoethyl}amino)‐6‐fluor o‐3,4‐dihydroquinazolin‐4‐one; (S)- 6‐({2‐[6,8‐dichloro‐1‐methyl‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl]‐2‐oxoethyl}amino)‐7‐fluoro‐1, 2‐dihydroisoquinolin‐1‐one; 7-fluoro-6-[[2-oxo-2-[(1S)-8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-1-one; 6-fluoro-2-methyl-7-[[2-oxo-2-[(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 2-amino-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6- fluoro-3H-quinazolin-4-one;73 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- phthalazin-1-one; 1-methyl-2-[2-[(1-oxo-2H-isoquinolin-6-yl)amino]acetyl]-3,4-dihydro-1H-isoquinoline-6- carbonitrile; 6-[[2-(1-methyl-6-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 6-fluoro-7-[[2-[1-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-7-[[2-[1-methyl-6-(1H-pyrazol-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-2-methyl-7-[[2-[1-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-2-methyl-7-[[2-[1-methyl-6-(1H-pyrazol-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-7-[[2-(6-isoxazol-4-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]- 2-methyl-3H-quinazolin-4-one; 7-[[2-[6-(3-aminophenyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6- fluoro-2-methyl-3H-quinazolin-4-one; 6-fluoro-2-methyl-7-[[2-[1-methyl-6-(3-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]- 3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]- 3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-(6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-oxo-2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-oxo-2-[(1R)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one;74 2-(3-aminopropylamino)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (4-hydroxybutylamino)-3H-quinazolin-4-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3-piperazin- 1-yl-2H-isoquinolin-1-one; 3-(2-aminoethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-2H-isoquinolin-1-one; 3-(aminomethyl)-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 3-[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1-oxo-2H- isoquinolin-3-yl]propanamide; 3-[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinolin-3-yl]propanenitrile; 3-(aminomethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(3-aminopropyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxybutyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3- [(dimethylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 3-(azetidin-3-yl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(3-aminopropyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-piperidyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (pyrrolidin-3-ylmethyl)-2H-isoquinolin-1-one; 3-(4-aminobutyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(3-aminopropyl)-7-fluoro-6-[[2-oxo-2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin-1-one;75 3-(3-aminopropyl)-7-fluoro-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (piperazin-1-ylmethyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (morpholinomethyl)-2H-isoquinolin-1-one; 3-(1-amino-1-methyl-ethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(1-aminocyclopentyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(1-aminocyclopropyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-piperidylmethyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-piperidyl)-2H-isoquinolin-1-one; 3-(aminomethyl)-6-[[2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1H-quinazoline-2,4- dione; 3-[6-[[2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-1-oxo-2H-isoquinolin-3-yl]propanamide; 3-(2-aminoethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-[7-fluoro-1-oxo-6-[[2-oxo-2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-3-yl]propanenitrile; 3-[7-fluoro-1-oxo-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-3-yl]propanenitrile; 3-[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinolin-3-yl]benzonitrile; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-pyridyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (3-pyridyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- pyrimidin-5-yl-2H-isoquinolin-1-one;76 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- thiazol-5-yl-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3-[4- (hydroxymethyl)phenyl]-2H-isoquinolin-1-one; 6-[[2-oxo-2-[(1S)-1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-oxo-2-[(1R)-1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin- 1-one; 2-(4-aminobutyl)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 2-(5-aminopentyl)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 2-(3-aminopropyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(4-aminobutyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(aminomethyl)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 2-(aminomethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- pyrrolidin-3-yl-3H-quinazolin-4-one; 2-(3-aminopropyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-[(R)-amino(cyclopropyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- piperazin-2-yl-3H-quinazolin-4-one; 2-[(1-aminocyclopropyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 3-(aminomethyl)-7-fluoro-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin- 2-yl]ethyl]amino]-2H-isoquinolin-1-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2- [(dimethylamino)methyl]-6-fluoro-3H-quinazolin-4-one; 2-(azetidin-1-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one;77 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2- (ethylaminomethyl)-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (piperazin-1-ylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (pyrrolidin-1-ylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2-hydroxyethylamino)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (morpholinomethyl)-3H-quinazolin-4-one; 2-[(4-acetylpiperazin-1-yl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2- (morpholinomethyl)-3H-quinazolin-4-one; 2-[(3-aminopropylamino)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[(2- fluoroethylamino)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[(2,2- difluoroethylamino)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[(2,2,2- trifluoroethylamino)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (4-piperidyl)-3H-quinazolin-4-one; 2-[(S)-amino(cyclopropyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-methylpiperazin-1-yl)methyl]-3H-quinazolin-4-one; 2-[(4-amino-1-piperidyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-piperidylamino)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- (piperazin-1-ylmethyl)-3H-quinazolin-4-one; 7-((2-((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((S)-pyrrolidin-3-yl)quinazolin-4(3H)-one78 7-((2-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((S)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-((2-((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((R)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-((2-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((R)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- pyrrolidin-3-yl-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (1-methyl-4-piperidyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2R)-morpholin-2-yl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2S)-morpholin-2-yl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(3R)-3-piperidyl]-3H-quinazolin-4-one; 2-(4-aminocyclohexyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(3S)-3-piperidyl]-3H-quinazolin-4-one; 2-(1-aminocyclopropyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (2-piperidylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (3-piperidylmethyl)-3H-quinazolin-4-one; 2-[(1R)-1-aminoethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(1S)-1-aminoethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(1R)-1-amino-2-methyl-propyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(1S)-1-amino-2-methyl-propyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(S)-amino(phenyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one;79 2-[(R)-amino(phenyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (4-hydroxycyclohexyl)-3H-quinazolin-4-one; 2-[(2R)-2-amino-2-cyclopropyl-ethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin- 2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 4-[7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-4- oxo-3H-quinazolin-2-yl]cyclohexanecarbonitrile; 2-(3-aminopropyl)-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(4-methylpiperazin-1-yl)methyl]-3H-quinazolin-4-one; 2-[(4-amino-1-piperidyl)methyl]-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3R)-pyrrolidin-3-yl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3S)-pyrrolidin-3-yl]-3H-quinazolin-4-one; 2-[(R)-amino(cyclopropyl)methyl]-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(3-oxopiperazin-1-yl)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-isopropylpiperazin-1-yl)methyl]-3H-quinazolin-4-one; 2-(1,4-diazepan-1-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(4,7-diazaspiro[2.5]octan-7-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl- 3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3S)-3-hydroxypyrrolidin-1-yl]methyl]-3H-quinazolin-4-one;80 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[4-hydroxy-4-(trifluoromethyl)-1-piperidyl]methyl]-3H-quinazolin-4-one; 1-[[7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro- 4-oxo-3H-quinazolin-2-yl]methyl]piperidine-4-carbonitrile; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[4-(oxetan-3-yl)piperazin-1-yl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[[3-(3,3- difluoroazetidin-1-yl)azetidin-1-yl]methyl]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-fluoropyrrolidin-1-yl]methyl]-3H-quinazolin-4-one; 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3H-quinazolin-4-one; 2-(4-aminobutyl)-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2R)-2-piperidyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (4-pyridyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (3-pyridyl)-3H-quinazolin-4-one; 2-[1-(aminomethyl)cyclopropyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(1S)-1,5-diaminopentyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (piperazin-2-ylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3H-quinazolin-4-one; 2-(aminomethyl)-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3-hydroxyazetidin-3-yl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3-hydroxy-3-piperidyl)methyl]-3H-quinazolin-4-one;81 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-hydroxy-4-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(4-hydroxy-4-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-1H- quinazoline-2,4-dione; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (hydroxymethyl)-3H-quinazolin-4-one; methyl 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-1-oxo-2H-isoquinoline-3-carboxylate; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinoline-3-carboxylic acid; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (morpholine-4-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxypiperidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxy-4-methyl-piperidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-methylpiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(3S)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- (oxetan-3-ylmethyl)-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-2,7-naphthyridin-1- one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- tetrahydrofuran-3-yl-3H-quinazolin-4-one; 2-[(1R)-1-amino-2-hydroxy-ethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one;82 3-[7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-4- oxo-3H-quinazolin-2-yl]propanenitrile; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxyethyl)-1-oxo-2H-isoquinoline-3-carboxamide; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- pyrazin-2-yl-3H-quinazolin-4-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N,N- dimethyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-N-(tetrahydrofuran-3-ylmethyl)-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-N-(tetrahydrofuran-3-ylmethyl)-2H-isoquinoline-3-carboxamide; 3-[(3S)-3-aminopyrrolidine-1-carbonyl]-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; N-(cyanomethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 3-(4,7-diazaspiro[2.5]octane-7-carbonyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3-[4- (oxetan-3-yl)piperazine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-fluoropyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 3-(3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; N-(2-aminoethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxyethyl)-N-methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-N-[2- (dimethylamino)ethyl]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinoline-3-carboxamide;83 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (hydroxymethyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxyethyl)-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (1-hydroxycyclopropyl)-2H-isoquinolin-1-one; 2-[[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro- 1-oxo-2H-isoquinolin-3-yl]methylamino]acetonitrile; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (methylaminomethyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(4-methylpiperazin-1-yl)methyl]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [[(3R)-3-fluoropyrrolidin-1-yl]methyl]-2H-isoquinolin-1-one; methyl 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1- oxo-2H-isoquinoline-4-carboxylate; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-4- (piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1-oxo-2H- isoquinoline-4-carbonitrile; 6-[[2-[8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- 3-(piperazin-4-ium-1-carbonyl)-2H-isoquinolin-1-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [((3S)-3-hydroxy-3-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [((3R)-3-hydroxy-3-piperidyl)methyl]-3H-quinazolin-4-one; (S)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro- 3H-quinazolin-4-one; 7-fluoro-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]- 3-(piperazine-1-carbonyl)-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]- 3-(piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-N-(2- hydroxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-4- (hydroxymethyl)isoquinolin-1(2H)-one;84 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-N-(2- (dimethylamino)ethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-N-methyl-1- oxo-1,2-dihydroisoquinoline-4-carboxamide; N-(cyanomethyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-1-oxo-1,2- dihydroisoquinoline-4-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-N,N- dimethyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 7-fluoro-6-[[2-[(1S)-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-(6-chloro-8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-(6-fluoro-1,8-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 7-fluoro-6-[[2-(8-fluoro-1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 7-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 6-fluoro-7-[[2-[(1S)-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 6-[[2-[(1S)-6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- 2H-isoquinolin-1-one; 7-[[2-(8-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 7-fluoro-6-[[2-(6-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-[6-(difluoromethoxy)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one; 6-[[2-(5-bromo-6-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-(6-fluoro-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-(6,8-dimethoxy-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro- 2H-isoquinolin-1-one;85 6-[[2-[(1S)-6-(difluoromethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-[1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-[(1S)-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-[(1R)-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-1-one; 6-[[2-[(1R)-8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-3-(3,3- difluoro-1,6-diazaspiro[3.3]heptane-6-carbonyl)-7-fluoroisoquinolin-1(2H)-one; 3-(2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 3-(2,5-diazabicyclo[4.1.0]heptane-2-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3- (4,7-diazaspiro[2.5]octane-4-carbonyl)isoquinolin-1(2H)-one; 3-(3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 3-[(3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carbonyl]-6-[[2-(6,8-dichloro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-N,N-dimethyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-N- (2-methoxyethyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(4- methyl-4,7-diazaspiro[2.5]octane-7-carbonyl)isoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(7- methyl-4,7-diazaspiro[2.5]octane-4-carbonyl)isoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(6- methyl-3,6-diazabicyclo[3.1.0]hexane-3-carbonyl)isoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-3-(3,3- difluoroazetidine-1-carbonyl)-7-fluoroisoquinolin-1(2H)-one;86 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (6-methyl-1,6-diazaspiro[3.3]heptane-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (1-methyl-1,6-diazaspiro[3.3]heptane-6-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2H-isoquinolin-1-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(3- fluoroazetidine-1-carbonyl)isoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-N- (3-fluorocyclobutyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-7-fluoro-3- (3-fluoro-[1,3'-biazetidine]-1'-carbonyl) isoquinolin-1(2H)-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(3,3- difluoropyrrolidine-1-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 3-[(3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carbonyl]-6-[[2-[(1S)-6-chloro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[3- (difluoromethyl)-3-hydroxy-pyrrolidine-1-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-methyl-3-oxo-piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(3,3- difluoroazetidine-1-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 3-[(3SR,4RS)-3-amino-4-(difluoromethyl)pyrrolidine-1-carbonyl]-6-[[2-[(1S)-6-chloro-1- methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-(1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-fluoropyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxyethyl)-N-methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-N-vinyl-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (morpholine-4-carbonyl)-2H-isoquinolin-1-one;87 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-isopropylpiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-methylpiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- N,N-dimethyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-N- (cyanomethyl)-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3S)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (3-oxopiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- (3-fluorocyclobutyl)-1-oxo-2H-isoquinoline-3-carboxamide; 3-[(3S)-3-aminopyrrolidine-1-carbonyl]-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(4,7- diazaspiro[2.5]octane-7-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 3-(4-acetylpiperazine-1-carbonyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[(5R)-1,4- diazabicyclo[3.2.1]octane-4-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[4-(2,2- difluoroethyl)piperazine-1-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [3-(trifluoromethyl)piperazine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(2,5- diazabicyclo[4.1.0]heptane-2-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[(1R,4R)- 2,5-diazabicyclo[2.2.2]octane-2-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[(1R,4R)- 2,5-diazabicyclo[2.2.2]octane-2-carbonyl]-7-fluoro-2H-isoquinolin-1-one;88 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [4-(2-hydroxyethyl)piperazine-1-carbonyl]-2H-isoquinolin-1-one; 3-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole-5-carbonyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxy-2-methyl-propyl)-N-methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(4,7- diazaspiro[2.5]octane-4-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- [(1-hydroxycyclopropyl)methyl]-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxypiperidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (3-hydroxyazetidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3S)-3-hydroxy-3-methyl-pyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-N-[2- (dimethylamino)-2-oxo-ethyl]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; (S)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-3-(piperazine-1-carbonyl)isoquinolin-1(2H)-one; (S)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-3-(4,7-diazaspiro[2.5]octane-4-carbonyl)isoquinolin-1(2H)-one; (S)-7-fluoro-N,N-dimethyl-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)- 2-oxoethyl)amino)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; 3-((S)-3-aminopyrrolidine-1-carbonyl)-7-fluoro-6-((2-((S)-1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 3-(3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-7-fluoro-6-((2-((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 3-(2,5-diazabicyclo[4.1.0]heptane-2-carbonyl)-7-fluoro-6-((2-((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-2-carbonyl)-2H-isoquinolin-1-one;89 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-4- [(dimethylamino)methyl]-2H-phthalazin-1-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-1- methyl-quinazoline-2,4-dione; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1-[2- (dimethylamino)ethyl]-6-fluoro-quinazoline-2,4-dione; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-1- (2-hydroxyethyl)quinazoline-2,4-dione; N-(2-(1H-pyrazol-3-yl)ethyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 4-((S)-3-aminopyrrolidine-1-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; methyl 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-1-oxo-2H-isoquinoline-4-carboxylate; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinoline-4-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-2H-isoquinoline-4-carboxamide; N-(cyanomethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-1-oxo-2H-isoquinoline-4-carboxamide; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-7-fluoro- 1-oxo-1,2-dihydroisoquinoline-4-carboxamide; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro- 4-(hydroxymethyl)isoquinolin-1(2H)-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- (pyrrolidin-3-ylmethyl)-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [[(3S)-3-piperidyl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3S)-3-piperidyl]methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3-hydroxypyrrolidin-3-yl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-piperidyl]methyl]-3H-quinazolin-4-one; (S)-2-(1-(aminomethyl)cyclopropyl)-7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl)amino)-6-fluoroquinazolin-4(3H)-one;90 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-piperidyl]methyl]-3H-quinazolin-4-one; (S)-2-(1-(aminomethyl)cyclopropyl)-6-fluoro-7-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)quinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- ((3-fluoroazetidin-1-yl)methyl)quinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-((3,3- difluoroazetidin-1-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- ((6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)quinazolin-4(3H)-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)methyl]-3H-quinazolin-4-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-((3,3- difluoro-1,6-diazaspiro[3.3]heptan-6-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- ((3-fluoro-[1,3'-biazetidin]-1'-yl)methyl)quinazolin-4(3H)-one; 6-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1`-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (hydroxymethyl)-2H-isoquinolin-1-one; 7-fluoro-6-[[2-[(1S)-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- (hydroxymethyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (hydroxymethyl)-2H-isoquinolin-1-one; 6-[[2-(6-chloro-8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-3-(hydroxymethyl)-2H-isoquinolin-1-one; 3-(aminomethyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (methylaminomethyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(dimethylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(cyclopropylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(cyclopropylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- (ethylaminomethyl)-7-fluoro-2H-isoquinolin-1-one;91 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(isopropylamino)methyl]-2H-isoquinolin-1-one; 3-[(tert-butylamino)methyl]-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2- oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(cyclopropylmethylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; (S)-3-((cyclobutylamino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)- yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; (S)-3-(aminomethyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-7-fluoroisoquinolin-1(2H)-one; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro- 3-((isopropylamino)methyl)isoquinolin-1(2H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- (piperazin-1-ylmethyl)quinazolin-4(3H)-one; (S)-6-((2-(6-chloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3- (methoxymethyl)isoquinolin-1(2H)-one; (S)-3-((tert-butylamino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)- 2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; (S)-3-(((cyclopropylmethyl)amino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-3- ((ethylamino)methyl)-7-fluoroisoquinolin-1(2H)-one; (S)-3-((cyclopropylamino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)- yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; (S)-3-((dimethylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-((ethylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-(((cyclopropylmethyl)amino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-(aminomethyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-3-((methylamino)methyl)isoquinolin-1(2H)-one; (S)-3-((cyclopropylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one;92 (S)-3-((cyclobutylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-((tert-butylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-7-fluoro-3-((isopropylamino)methyl)-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]methyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]methyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[(oxetan-3-ylamino)methyl]-2H-isoquinolin-1-one; 1-[[[6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-1-oxo-2H-isoquinolin-3-yl]methylamino]methyl]cyclopropanecarbonitrile; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[[(1-fluorocyclobutyl)methylamino]methyl]-2H-isoquinolin-1-one; or 3-[[[(1S)-1-cyclopropyl-2,2,2-trifluoro-ethyl]amino]methyl]-6-[[2-[(1S)-6,8-dichloro-1-methyl- 3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one.

[0175] The various functional groups and substituents making up the compounds of the Formula (I) or (II) are typically chosen such that the molecular weight of the compound of the Formula (I) or (II) 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.

[0176] 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.

[0177] 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 termed93 “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 a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0178] 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 antiproliferative activity.

[0179] 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.

[0180] It is also to be understood that certain compounds of the Formula (I) or (II) (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 antiproliferative activity.

[0181] It is also to be understood that certain compounds of the Formula (I) or (II) (and compounds of subformulas thereof) may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.94

[0182] Compounds of the Formula (I) or (II) (and compounds of subformulas thereof) may exist in a number of different tautomeric forms and references to compounds of the Formula (I) or (II) 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) or (II). 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. H O OH H+O-keto enol enolate

[0183] Compounds of the Formula (I) or (II) containing an amine function may also form N- oxides. A reference herein to a compound of the Formula (I) or (II) 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.

[0184] The compounds of Formula (I) or (II) 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) or (II) 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) or (II).

[0185] Accordingly, the present invention includes those compounds of the Formula (I) or (II) 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.95 Accordingly, the present invention includes those compounds of the Formula (I) or (II) 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) or (II) may be a synthetically-produced compound or a metabolically- produced compound.

[0186] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) or (II) 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.

[0187] 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.

[0188] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) or (II) 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) or (II) 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,96 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.

[0189] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) or (II) 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) or (II) 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 ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0190] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) or (II) 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.

[0191] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) or (II) 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, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl.

[0192] The in vivo effects of a compound of the Formula (I) or (II) may be exerted in part by one or more metabolites that are formed within the human or animal body after97 administration of a compound of the Formula (I) or (II). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) or (II) may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0193] 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.

[0194] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein. Synthesis

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.98

[0200] 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.

[0201] 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 a suitable 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.

[0202] 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.

[0203] 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.

[0204] Resins may also be used as a protecting group.99

[0205] The methodology employed to synthesise a compound of Formula (I) or (II) will vary depending on the nature of the variable groups. Suitable processes for their preparation are described further in the accompanying Examples.

[0206] Once a compound of Formula (I) or (II) 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) or (II) into another compound of Formula (I) or (II); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0207] The resultant compounds of Formula (I) or (II) can be isolated and purified using techniques well known in the art. Biological Activity

[0208] 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.

[0209] Although the pharmacological properties of the compounds of Formula (I) or (II) vary with structural change, as expected, the compounds of the invention were found to be active in these METTL1 assays.

[0210] In general, the compounds of the invention demonstrate an IC50 of 100 µM or less in the METTL1 enzyme assay described herein, with particularly preferred compounds of the invention demonstrating an IC50 of 1 µM or less and the most preferred compounds of the invention demonstrating an IC50 of 0.1 µM or less.

[0211] In the METTL1 cell assay described in the Example section, the compounds of Formula (I) or (II) may suitably possess an IC50 of less than 45 µM (e.g. less than 40 µM), with particularly preferred compounds of the invention demonstrating an IC50 of 10 µM or less and the most preferred compounds demonstrating an activity of 2 µM or less.

[0212] 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 5 µM or less and the most preferred compounds demonstrating an activity of 2 µM or less.100

[0213] 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

[0214] 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.

[0215] 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).

[0216] 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.

[0217] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition and / or disease. The proliferative condition may be selected from any of those described herein.

[0218] 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.

[0219] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) or (II) will naturally vary according to the nature and severity of the101 conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0220] 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

[0221] The present invention provides compounds that function as inhibitors of METTL1 activity.

[0222] 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.

[0223] 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.

[0224] Suitably, the disease or disorder in which METTL1 activity is implicated is cancer.

[0225] 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),102 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.

[0226] 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); Primary effusion lymphoma (PEL).

[0227] 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;103 ^ 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).

[0228] More suitably the cancer is selected from lung cancer (including non-small cell lung cancer), renal cancer, solid organ cancer, pancreactic cancer (including , pancreatic adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer (including invasive breast carcinoma), bladder cancer, hepatocellular carcinoma, hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma), nasopharyngeal carcinoma, sarcoma, glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B-cell neoplasm, esophagogastric adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, ovarian epithelial tumor, prostate adenocarcinoma, cervical squamous cell carcinoma, renal clear cell carcinoma, non-clear cell carcinoma or cervical adenocarcinoma.

[0229] 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 salt104 thereof, or a pharmaceutical composition as defined herein.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.105

[0234] Suitably the cancer is lung cancer (including non-small cell lung cancer), renal cancer, solid organ cancer, pancreactic cancer (including , pancreatic adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer (including invasive breast carcinoma), bladder cancer, hepatocellular carcinoma, hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma), nasopharyngeal carcinoma, sarcoma, glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B-cell neoplasm, esophagogastric adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, ovarian epithelial tumor, prostate adenocarcinoma, cervical squamous cell carcinoma, renal clear cell carcinoma, non-clear cell carcinoma or cervical adenocarcinoma..

[0235] 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); Primary effusion lymphoma (PEL).

[0236] 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 including106 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).

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0243] 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.

[0244] 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-cancerous107 tumour growth is ameloblastoma.

[0245] 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.

[0246] 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.

[0247] Suitably the cancer is lung cancer (including non-small cell lung cancer), renal cancer, solid organ cancer, pancreactic cancer (including , pancreatic adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer (including invasive breast carcinoma), bladder cancer, hepatocellular carcinoma, hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma), nasopharyngeal carcinoma, sarcoma, glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B-cell neoplasm, esophagogastric adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, ovarian108 epithelial tumor, prostate adenocarcinoma, cervical squamous cell carcinoma, renal clear cell carcinoma, non-clear cell carcinoma or cervical adenocarcinoma.

[0248] 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 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); Primary effusion lymphoma (PEL).

[0249] 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).

[0250] 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.

[0251] Suitably, the leukaemia may be any of the leukaemias described herein, for example acute myeloid leukaemia (AML) including acute monoblastic / monocytic leukemia,109 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] Suitably, the disease or disorder in which METTL1 activity is implicated is cancer.

[0257] 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), adrenocortical110 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.

[0258] Suitably, the cancer is selected from lung cancer (including non-small cell lung cancer), renal cancer, solid organ cancer, pancreactic cancer (including , pancreatic adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer (including invasive breast carcinoma), bladder cancer, hepatocellular carcinoma, hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma), nasopharyngeal carcinoma, sarcoma, glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B-cell neoplasm, esophagogastric adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, ovarian epithelial tumor, prostate adenocarcinoma, cervical squamous cell carcinoma, renal clear cell carcinoma, non-clear cell carcinoma or cervical adenocarcinoma.

[0259] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in increasing or enhancing an anti-tumour response to radiotherapy. The present invention provides a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the inhibition of metastasis in vivo.

[0260] 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.

[0261] 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.

[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; acute111 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.

[0263] Suitably the cancer is lung cancer (including non-small cell lung cancer), renal cancer, solid organ cancer, pancreactic cancer (including , pancreatic adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer (including invasive breast carcinoma), bladder cancer, hepatocellular carcinoma, hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma), nasopharyngeal carcinoma, sarcoma, glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B-cell neoplasm, esophagogastric adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, ovarian epithelial tumor, prostate adenocarcinoma, cervical squamous cell carcinoma, renal clear cell carcinoma, non-clear cell carcinoma or cervical adenocarcinoma.

[0264] 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 any of those described herein.

[0265] 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 any of those described herein.112

[0266] 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.

[0267] 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.

[0268] 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 hepatocellular carcinoma.

[0269] 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.

[0270] 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. The cancer may be any of the cancers described herein. Suitably, the cancer is selected from lung cancer (including non-small cell lung cancer), renal cancer, solid organ cancer, pancreactic cancer (including , pancreatic adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer (including invasive breast carcinoma), bladder cancer, hepatocellular carcinoma, hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma), nasopharyngeal carcinoma, sarcoma, glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B-cell neoplasm, esophagogastric adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, ovarian epithelial tumor, prostate adenocarcinoma, cervical squamous cell carcinoma, renal clear cell carcinoma, non-clear cell carcinoma or cervical adenocarcinoma. 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. 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 metastasis in vivo.

[0271] The term "proliferative disorder" are used interchangeably herein and pertain113 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), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain and skin.

[0272] 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).

[0273] 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). 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

[0274] 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.114

[0275] Thus, 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.

[0276] 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.

[0277] 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.

[0278] 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 5^-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-6-115 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-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol.54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example 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), erbB2 tyrosine 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 ^v^3 function and angiostatin)];116 (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)).

[0279] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery, radiotherapy or chemotherapy.

[0280] 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;117 ^ immune checkpoint inhibitors such as PD1 inhibitors and CTLA4 inhibitors.

[0281] In a particular embodiment, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with radiotherapy.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.118

[0290] 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.

[0291] 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 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] In another embodiment, the invention relates to a therapeutic combination comprising a compound as defined herein and another agent used to treat AML leukeamia119 e.g., cytarabine, FLT3 inhibitors, BCL2 inhibitors or IDH1 / 2 inhibitors.

[0297] The combinations described above may be utilised in the treatment of any of the diseases or disorders described herein. Examples

[0298] Compounds of Formula (I) and (II) 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) and (II) 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. General Procedures

[0299] 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 K using 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). LCMS Methods

[0300] Analytical Method 1 (M1) HPLC-MS were performed in reverse phase using a Kinetex Core shell C18 column (2.1 mm × 50 mm, 5 µm; temperature: 40 °C), with an injection volume of 3 µL at a flow rate of 1.2 mL / min and a gradient of 5 – 100% B over 1.2 min, then 100% B for 0.1 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in MeCN. A second gradient of 100 – 5% B was then applied over 0.01 min and held for 0.39 min. UV spectra were recorded at 215 nm; spectrum range: 210 – 420 nm. Mass spectra were obtained using a 2010EV or a Waters ZQ detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Shimadzu LCMS- Solutions and PsiPort software or Waters MassLynx and OpenLynx software.

[0301] Analytical Method 2 (M2) UHPLC-MS were performed in reverse phase system using a Waters UPLCTMBEHTMC18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.9 mL / min and a gradient of 5 – 100% B over 1.1 min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in MeCN. A second gradient of 100 – 5% B was then applied over 0.05120 min and held for 0.1 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters SQD or QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0302] Analytical Method 3 (M3) UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.3 min, then 100% B for 0.5 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in MeCN. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD or QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0303] Analytical Method 4 (M4) UHPLC-MS were performed in reverse phase using a Waters UPLCTMBEHTMC18 column (2.1 mm × 30 mm, 1.7 µm; temperature 40 °C), with an injection volume of 1 µL at a flow rate of 1.0 mL / min and a gradient of 1 – 100% B over 1.1 min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = MeCN. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.4 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0304] Analytical Method 5 (M5) UHPLC-MS were performed in reverse phase using a Waters UPLCTMBEHTMC18 column (2.1 mm × 30 mm, 1.7 µm; temperature 55 °C), with an injection volume of 1 µL at a flow rate of 1.0 mL / min and a gradient of 1 – 100% B over 1.1 min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = MeCN. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.4 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0305] Analytical Method 6 (M6) UHPLC-MS were performed in reverse phase using a Waters UPLCTMBEHTMC18 column (2.1 mm × 100 mm, 1.7 µm column; temperature: 40 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.3 min, then 100% B for 0.5 min, where A = 2 mM ammonium121 bicarbonate in water, buffered to pH 10, and B = MeCN. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0306] Analytical Method 7 (M7) UHPLC-MS were performed in reverse phase using a Waters UPLCTMBEHTMC18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 55 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.3 min, then 100% B for 0.5 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = MeCN. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0307] Analytical Method 8 (M8) UHPLC-MS were performed in reverse phase using a Waters UPLCTMBEHTMC18 column (2.1 mm × 30 mm, 1.7 µm; temperature: 40 °C), with an injection volume of 1 µL at a flow rate of 1 mL / min and a gradient of 5 – 100% B over 0.75 min, then 100% B for 0.1 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = MeCN. A second gradient of 100 – 5% B was then applied over 0.05 min and held for 0.1 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0308] Analytical Method 9 (M9) HPLC-MS were performed in reverse phase using a Waters AtlantisTMdC18 column (2.1 mm × 100 mm, 3 µm; temperature: 40 °C), with an injection volume of 3 µL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5 min, then 100% B for 0.4 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in MeCN. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.58 min. UV spectra were recorded at 215 nm; spectrum range: 210 – 400 nm. Mass spectra were obtained using a 2010EV detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0309] Analytical Method 10 (M10) UHPLC-MS were performed in reverse phase using a Waters UPLC® BEH C18 column (2.1 mm × 50 mm, 2.5 µm; temperature: 25 °C), with an injection volume of up to 10 µL at a flow rate of 0.8 mL / min and a gradient of 3 –122 100% B over 3 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in water:MeCN (10:90). A second gradient of 100 – 3% B was then applied over 0.01 min and held for 0.49 min. UV spectra were recorded in spectrum range: 200 – 400 nm. Mass spectra were obtained using a QDa detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Empower 3 software.

[0310] Analytical Method 11 (M11) HPLC were performed in reverse phase using an Atlantis C18 column (4.6 mm × 150 mm, 5 µm; temperature: 25 °C), with an injection volume of up to 100 µL at a flow rate of 1 mL / min and a gradient of 10 – 100% B over 9 min and held at 100% for 5 min, where A = 0.1% ammonia in water, and B = MeCN. A second gradient of 100 – 10% B was then applied over 0.01 min and held for 2.59 min. UV spectra were recorded in spectrum range: 200 – 400 nm. Data were integrated and reported using Empower 3 software.

[0311] Analytical Method 12 (M12) HPLC were performed in reverse phase using an Xtimate C18 column (4.6 mm × 150 mm, 5 µm; temperature: 25 °C), with an injection volume of up to 100 µL at a flow rate of 1 mL / min and a gradient of 10 – 100% B over 9 min and held at 100% for 5 min, where A = 0.05% TFA in water, and B = MeCN. A second gradient of 100 – 10% B was then applied over 0.01 min and held for 2.59 min. UV spectra were recorded in spectrum range: 200 – 400 nm. Data were integrated and reported using Openlab software.

[0312] Analytical Method 13 (M13) SFC analysis were performed on a Waters Thar SFC using a Chiralcel OJ-H column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 30:700.2% DEA in MeOH:CO2 over 5 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 215 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0313] Analytical Method 14 (M14) SFC analysis were performed on a Waters Thar SFC using a Chiralpak AS-H, (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 15:850.2% DEA in MeOH:CO2over 40 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 215 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0314] Analytical Method 15 (M15) SFC analysis were performed on a Waters Thar SFC using a Chiralpak AD-H column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 35:65 EtOH:CO2over 10 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 254 nm using a Waters123 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0315] Analytical Method 16 (M16) refers to an LC analysis performed on a Waters ARC LC system using an Amylose-2 column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 0.2% DEA in EtOH over 50 mins, with an injection volume of 10 µL and a flow rate of 1 mL / min. UV spectra were recorded at 260 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0316] Analytical Method 17 (M17) SFC analysis were performed on a Waters Thar SFC using a Chiralpak AD-H column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 40:600.2% DEA in IPA:CO2 over 10 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 254 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0317] Analytical Method 18 (M18) SFC analysis were performed on a Waters Thar SFC using a Chiralpak AD-H column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 30:700.2% DEA in IPA:CO2 over 25 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 254 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0318] Analytical Method 19 (M19) SFC analysis performed on a Waters Thar SFC using a Chiralpak AD-H column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 25:750.2% DEA in MeOH:CO2 over 60 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 265 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0319] Analytical Method 20 (M20) refers to an LC analysis performed on a Waters ARC LC system using a Chiralpak AD-H column (4.6 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of EtOH over 20 mins, with an injection volume of 10 µL and a flow rate of 1 mL / min. UV spectra were recorded at 260 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0320] Analytical Method 21 (M21) refers to an LC analysis performed on a Waters ARC LC system using a Cellulose-4 column (4.6 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of 50:50 MeOH:EtOH over 20 mins, with an injection volume of 10 µL and a flow rate of 1 mL / min. UV spectra were recorded at 270 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.124

[0321] Analytical Method 22 (M22) refers to SFC analysis performed on a Waters Investigator SFC using a Chiralpak IG column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 30:700.2% DEA in MeCN:CO2over 60 mins, with an injection volume of 20 µL and a flow rate of 3 mL / min. UV spectra were recorded at 220 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters Chromscope software.

[0322] Analytical Method 23 (M23) SFC analysis were performed on a Waters Thar SFC using a Chiralpak AD-H column (4.6 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 30:70 MeOH:CO2 over 8 mins, with an injection volume of 10 µL and a flow rate of 4 mL / min, back pressure of 120 bar. UV spectra were recorded at 260 nm using a Waters 2998 photo diode array detector. Data were integrated using Waters MassLynx and OpenLynx software.

[0323] Analytical Method 24 (M24) UHPLC-MS were performed in reverse phase using a Waters UPLC® BEH C18 column (2.1 mm × 50 mm, 2.5 µm; temperature: 25 °C), with an injection volume of up to 10 µL at a flow rate of 0.55 mL / min and a hold of 5% B over 0.4 min with a gradient of 5 – 35% B over 0.4 min followed by 35 – 55% B over 0.4 min, where A = 2 mM ammonium acetate and 0.1% formic acid in water, and B = 0.1% formic acid in MeCN. Another gradient of 55 – 100% B over 1.3 min was then applied followed by a hold of 100% B over 0.8 min with another gradient of 100 – 5% B over 0.7 min. UV spectrum range 210 – 400 nm.

[0324] Analytical Method 25 (M25) SFC analysis was performed on a Waters SFC Investigator system using a Chiralpak IG column (4.6 mm x 250 mm, 5 µm) at 40 °C and an isocratic eluent of 10:900.1% (7 N ammonia in MeOH) in MeOH:CO2, with a flow rate of 3 mL / min. UV spectra were recorded using a Waters 2998 PDA detector. Preparative HPLC

[0325] Preparative Method 1 (P1): Purification LC were performed in reverse phase using a Waters SunfireTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10 – 95% B over 14.1 min and held for 1.9 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in MeCN. A second gradient of 95 – 10% B was then applied over 0.3 min and held for a further 0.9 min. UV spectra were recorded at 215 nm.

[0326] Preparative Method 2 (P2): Purification LC were performed in reverse phase using a Waters SunfireTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for125 1.9 min then a gradient of 30 – 95% B over 9.6 min and held for 2.0 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in MeCN. A second gradient of 95 – 30% B was then applied over 0.3 min and held for 1.3 min. UV spectra were recorded at 215 nm.

[0327] Preparative Method 3 (P3): Purification LC were performed in reverse phase using a Waters XBridgeTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 2.0 min then a gradient of 10 – 95% B over 14.0 min and held for 2.0 min, where A = 0.2% ammonium hydroxide in water and B = 0.2% ammonium hydroxide in MeCN. A second gradient of 95 – 10% B was then applied over 0.2 min and held for 0.9 min. UV spectra were recorded at 215 nm.

[0328] Preparative Method 4 (P4): Purification LC were performed in reverse phase using a Waters XBridgeTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 2.0 min then a gradient of 30 – 95% B over 9.5 min and held for 2.0 min, where A = 0.2% ammonium hydroxide in water and B = 0.2% ammonium hydroxide in MeCN. A second gradient of 95 – 30% B was then applied over 0.3 min and held for 1.3 min. UV spectra were recorded at 215 nm.

[0329] Preparative Method 5 (P5): Purification LC were performed in reverse phase using a Waters XBridgeTMC18 OBD column (19 mm × 250 mm, 5 μm; temperature: room temperature), with a flow rate of 18 mL / min with an isocratic mobile phase of 48% B for 15.0 min then held at an isocratic mobile phase of 98% B for 2.0 min, where A = 0.05% ammonium hydroxide in water and B = MeCN. A second isocratic mobile phase of 45% B was then held for 3 min. UV spectra were recorded at 215 nm.

[0330] Preparative Method 6 (P6): Purification LC were performed in reverse phase using a Phenomenex Xtimate C18 column (19 mm × 250 mm, 5 μm; temperature: room temperature), with a flow rate of 20 mL / min with a gradient of 40 – 45% B over 16 min followed by a gradient of 45 – 98% B over 0.01 min and a hold at 98% B over 2.0 min, where A = 0.05% ammonium hydroxide in water and B = MeCN. A further gradient of 98 – 40% B was then applied over 0.01 min, followed by a hold at 40% B for 3.59 min. UV spectra were recorded at 210 and 254 nm. Chiral separation methods

[0331] Chiral Separation Method 1 (C1): LC separation performed on an Agilent 1260 Infinity-II LC system using a Chiralpak IG column (21 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of 95:5 MeCN:IPA over 35 mins, with an injection volume of 5 mL and a flow rate of 25 mL / min. UV spectra were recorded in spectrum range 200 – 400 nm126 using an Agilent 1260 Infinity-II photo diode array detector.

[0332] Chiral Separation Method 2 (C2): SFC separation performed on a Waters SFC 350 system using a Chiralpak IG column (50 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of 30:700.1% DEA in MeCN:MeOH:IPA:MTBE (70:10:10:10):CO2over 11 mins, with an injection volume of 2 mL and a flow rate of 170 mL / min. UV spectra were recorded in spectrum range 200 – 400 nm using a Waters 2489 UV detector.

[0333] Chiral Separation Method 3 (C3): SFC separation performed on a Waters Thar SFC system using a Chiralpak AD-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 40:600.2% DEA in IPA:CO2, with a flow rate of 15 mL / min.

[0334] Chiral Separation Method 4 (C4): SFC separation performed on a Waters Thar SFC system using a Chiralpak AD-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 25:750.2% DEA in IPA:CO2, with a flow rate of 15 mL / min.

[0335] Chiral Separation Method 5 (C5): SFC separation performed on a Waters Thar SFC system using a Chiralpak AD-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 25:750.2% DEA in MeOH:CO2, with a flow rate of 15 mL / min.

[0336] Chiral Separation Method 6 (C6): LC separation performed on a Gilson LC system using a Chiralpak AD-H column (20 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of EtOH, with a flow rate of 9 mL / min.

[0337] Chiral Separation Method 7 (C7): LC separation performed on a Gilson LC system using a Cellulose-4 column (21.2 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of 50:50 MeOH:EtOH, with a flow rate of 9 mL / min.

[0338] Chiral Separation Method 8 (C8): SFC separation performed on a Waters Thar SFC system using a Chiralpak AD-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 35:650.2% DEA in EtOH:CO2, with a flow rate of 15 mL / min.

[0339] Chiral Separation Method 9 (C9): SFC separation performed on a Waters Thar SFC system using a Chiralpak AS-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 15:850.2% DEA in MeOH:CO2, with a flow rate of 15 mL / min.

[0340] Chiral Separation Method 10 (C10): SFC separation performed on a Waters Thar SFC system using a Chiralpak AD-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 35:65 EtOH:CO2, with a flow rate of 15 mL / min.

[0341] Chiral Separation Method 11 (C11): LC separation performed on a Gilson LC system using an Amylose-2 column (21.2 mm × 250 mm, 5 µm) at 25 °C and an isocratic eluent of 0.2% DEA in EtOH, with a flow rate of 18 mL / min.127

[0342] Chiral Separation Method 12 (C12): SFC separation performed on a Waters Thar SFC system using a Chiralpak AD-H column (10 mm × 250 mm, 5 µm) at 40 °C and an isocratic eluent of 30:70 MeOH:CO2, with a flow rate of 15 mL / min.

[0343] Chiral Separation Method 13 (C13): LC separation performed on a Shimadzu LC system using a Chiralpak AD-H column (20 mm x 250 mm, 5 µm) at ambient temperature and an isocratic eluent of 85:15 heptane:0.2% DEA in EtOH, with a flow rate of 18 mL / min.

[0344] Chiral Separation Method 14 (C14): LC separation performed on an Agilent 1260 Infinity II prep HPLC with UV detector using a Chiralpak IG column (20 mm x 250 mm, 5 µm) at ambient temperature and an isocratic eluent of 0.1% (7 N ammonia in MeOH) in MeCN, with a flow rate of 25 mL / min.

[0345] Where compounds were purified by liquid chromatography, a Biotage Isolera™ chromatography system using pre-packed silica and pre-packed modified silica cartridges was used. Abbreviations AcOH Acetic acid Bn Benzyl BOC tert-Butyloxycarbonyl Br Broad BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-tri-iso-propyl-1,1′- biphenyl BrettPhos.Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-iso-propyl-1,1′- biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate ca. Circa dba Dibenzylideneacetone DCE 1,2-Dichloroethane DCM Dichloromethane DEA Diethylamine DIBAL Di-iso-butylaluminium hydride DIPEA N,N-Di-iso-propylethylamine DMA Dimethylacetamide DMF Dimethylformamide DMSO Dimethylsulfoxide dppf 1,1′-bis(Diphenylphosphino)ferrocene128 ELS Electrospray EtOAc EtOAc EtOH Ethanol HATU (1-[bis(Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl Hydrochloric acid HPLC High pressure liquid chromatography Hz Hertz IPA iso-Propyl alcohol L Litres LC Liquid chromatography LDA Lithium di-iso-propylamide Me Methyl MeCN Acetonitrile MeOH Methanol MHz Mega Hertz Min Minutes mL Millilitre mmol Millimole MS Mass spectrometry Ms Methanesulfonic MTBE Methyl tert-butyl ether N Normal NBS N-Bromosuccinimide NMP N-Methyl-2-pyrrolidone OtBu tert-Butoxide Pd-C Palladium on charcoal PPA Polyphosphoric acid pTSA para-Toluene sulfonic acid Py Pyridine quant Quantitative rcf Relative centrifugal force RT Room temperature SCX Strong cation exchange SFC Supercritical fluid chromatography SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl129 STAB Sodium triacetoxyborohydride T3P Propylphosphonic anhydride TBAC N,N,N-Tributylbutan-1-aminium chloride TEA Triethylamine Tf Triflate TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TMOF Trimethyl orthoformate Tol Toluene tR Retention time UHPLC Ultra high performance liquid chromatography UPLC Ultra performance liquid chromatography XantPhos 4,5-bis(Diphenylphosphino)-9,9-dimethylxanthene Synthesis of Intermediates Intermediate route 1 exemplified by the synthesis of 2-amino-1-(1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)ethanone (Intermediate 1)

[0346] To a solution of N-(tert-butoxycarbonyl)glycine (5.68 g, 32.4 mmol) and triethylamine (7.6 mL, 54.3 mmol) in THF (80 mL) was added HATU (15.51 g, 40.8 mmol) and the reaction mixture was stirred at ambient temperature for 5 mins before 1-methyl- 1,2,3,4-tetrahydroisoquinoline (4.00 g, 27.2 mmol) was added and stirring continued at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude reaction mixture partitioned between saturated sodium bicarbonate solution (50 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer extracted into EtOAc (2 x 50 mL). The organic layers were combined and washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude material as a yellow oil. Purification by silica gel chromatography eluting with 10 – 60% EtOAc in heptane gave the desired compound; tert-butyl N-[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]carbamate (Intermediate 143) (7.60 g, 90%) as a viscous, colourless oil. LCMS (Analytical Method M9) tR = 4.05 min, [M+H]+= 305.1; 1H NMR (500 MHz, DMSO-d6) δ 7.26 – 7.13 (m, 4H), 6.79 (dt, J = 11.4, 5.8 Hz, 1H), 5.42 (q, J = 6.7 Hz, 1H), 3.92 – 3.77 (m, 3H), 3.47 – 3.42 (m, 1H), 2.94 – 2.69 (m, 2H), 1.39 (s, 9H), 1.35 (d, J = 6.8 Hz, 3H).130

[0347] tert-Butyl N-[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]carbamate (Intermediate 143) (7.76 g, 25.5 mmol) was suspended in 4 N HCl in 1,4- dioxane (78 mL) at room temperature and the reaction mixture was stirred for 5 hours. The reaction mixture was concentrated in vacuo and redissolved in MeOH (ca. 5 mL). The compound was loaded onto an SCX cartridge, the cartridge was flushed with MeOH (50 mL) and the desired compound was eluted with 7 N ammonia in MeOH (50 mL). The ammonia / MeOH filtrate was concentrated in vacuo to give the desired product; 2-amino-1- (1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (Intermediate 1) (5.00 g, 86%) as a yellow oil. LCMS (Analytical Method M7) tR = 2.06 min, [M+H]+= 205.4; 1H NMR (500 MHz, MeOD) δ 7.25 – 7.13 (m, 4H), 5.55 (q, J = 6.8 Hz, 1H), 3.82 – 3.74 (m, 1H), 3.72 – 3.62 (m, 2H), 3.60 – 3.51 (m, 1H), 3.01 – 2.82 (m, 2H), 1.56 (d, J = 6.8 Hz, 1H), 1.46 (d, J = 6.8 Hz, 2H), NH2 not observed.

[0348] The following intermediates were synthesised according to the above method from commercially available tetrahydroisoquinolines or those prepared by chiral separation as detailed in intermediate route 4 below, ,131 isoquinolin-2-yl)ethanone 241.1yl]ethyl]carbamate (Isomer 1)132 Intermediate route 2 exemplified by the synthesis of 2-bromo-1-(1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)ethanone (Intermediate 8)

[0349] To a solution of 1-methyl-1,2,3,4-tetrahydroisoquinoline (5.0 mL, 35.0 mmol) in DCM (150 mL) at 0 °C was added bromoacetyl bromide (9.0 mL, 0.103 mol) dropwise and the reaction mixture was stirred at 0 °C for 10 mins before allowing the reaction mixture to warm to room temperature for 5 hours. The reaction mixture was cooled to 0 °C and bromoacetyl bromide (9.0 mL, 0.103 mol) was added dropwise and stirring continued for a further 72 hours. The reaction mixture was quenched by the addition of 1 M HCl (20 mL), the layers were separated and the aqueous layer was re-extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude material was purified by silica gel chromatography eluting with 0 – 20% EtOAc in heptanes to yield 2- bromo-1-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (Intermediate 8) (6.00 g, 63%) as a yellow oil. LCMS (Analytical Method M7) tR = 2.95 min, [M+H]+= 270.1 / 271.2; 1H NMR (400 MHz, DMSO-d6) δ 7.23 – 7.11 (m, 4H), 5.50 – 5.33 (m, 1H), 4.25 – 4.11 (m, 2H), 3.98 – 3.89 (m, 2H), 3.06 – 2.73 (m, 2H), 1.58 – 1.32 (m, 3H). Intermediate route 3 exemplified by the synthesis of 2-[(1-oxo-2H-isoquinolin-6- yl)amino]acetic acid (Intermediate 9)

[0350] To a degassed mixture of methyl glycinate hydrochloride (408 mg, 3.25 mmol), 6-bromo-2H-isoquinolin-1-one (500 mg, 2.16 mmol) and sodium tert-butoxide (416 mg, 4.33 mmol) in DMF (10 mL) was added BrettPhos Pd G3 (197 mg, 0.217 mmol) and the reaction mixture was sparged with N2and heated to 100 °C for 2 hours. Additional amounts of sodium tert-butoxide (416 mg, 4.33 mmol) and BrettPhos Pd G3 (197 mg, 0.217 mmol) were added and heating continued at 100 °C for 2 hours. The resulting brown suspension was filtered and concentrated in vacuo to give the crude material which was purified by C18 reverse phase chromatography eluting with 10 – 100% 0.1% formic acid in MeCN in 0.1% formic acid in water to give methyl 2-[(1-oxo-2H-isoquinolin-6-yl)amino]acetate (Intermediate 150) (275 mg, 44%), as a white solid. LCMS (Analytical Method M9) tR = 2.69 min, [M+H]+= 233.0; 1H NMR (500 MHz, DMSO-d6) δ 10.69 (d, J = 4.1 Hz, 1H), 7.88 (d, J =133 8.8 Hz, 1H), 6.99 (dd, J = 7.1, 5.9 Hz, 1H), 6.80 (dd, J = 8.8, 2.3 Hz, 1H), 6.75 (t, J = 6.4 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 6.27 (d, J = 7.1 Hz, 1H), 4.04 (d, J = 6.3 Hz, 2H), 3.67 (s, 3H).

[0351] To a solution of methyl 2-[(1-oxo-2H-isoquinolin-6-yl)amino]acetate (Intermediate 150) (270 mg, 1.16 mmol) in water:MeOH (6 mL, 1:1, v:v) was added sodium hydroxide (233 mg, 5.81 mmol) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the resulting suspension acidified to pH 4 with 2 N HCl. The solid was collected by filtration and washed with diethyl ether (3 x 5 mL) and oven dried to give 2-[(1-oxo-2H-isoquinolin-6-yl)amino]acetic acid (Intermediate 9) (238 mg, 74%) as a white solid. LCMS (Analytical Method M3) tR = 1.15 min, [M+H]+= 219.1; 1H NMR (500 MHz, DMSO-d6) δ 10.72 (d, J = 4.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.03 – 6.95 (m, 1H), 6.81 (dd, J = 8.8, 2.3 Hz, 1H), 6.47 (d, J = 2.2 Hz, 1H), 6.28 (d, J = 7.1 Hz, 1H), 3.92 (s, 2H), NH and acidic OH not observed. Intermediate route 4 exemplified by the synthesis of 6-chloro-8-fluoro-1-methyl-1,2,3,4- tetrahydroisoquinoline (Intermediate 252) and 8-chloro-6-fluoro-1-methyl-1,2,3,4- tetrahydroisoquinoline (Intermediate 14)

[0352] To a stirred solution of 3-chloro-5-fluorobenzaldehyde (50 g, 316.4 mmol) in acetic acid (550 mL) was added ammonium acetate (56.10 g, 727.8 mmol) and nitromethane (55.06 g, 901.8 mmol) and the reaction mixture was heated to reflux at 120 °C for 5 hours. The reaction mixture was poured onto ice cold water (700 mL) and extracted into EtOAc (3 x 500 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo to obtain the crude material which was purified by silica gel chromatography eluting with 0.7% EtOAc in n-hexane to afford 1-chloro-3-fluoro-5-(2-nitrovinyl)benzene (Intermediate 247) (107.0 g, 42%).1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 13.6 Hz, 1H), 8.12 (d, J = 13.6 Hz, 1H), 7.89 (s, 1H), 7.83 – 7.80 (m, 1H), 7.63 (dt, J = 8.4, 2.4 Hz, 1H).

[0353] To an ice cooled solution of 1-chloro-3-fluoro-5-(2-nitrovinyl)benzene (Intermediate 247) (25.0 g, 1.24 mol) in MeOH (2.5 L) was added 1.2 M HCl in EtOH (250 mL) and the reaction mixture was stirred at 0 °C for 30 mins. 10% Palladium on charcoal (25.0 g) was added to the reaction mixture and the suspension was sparged with hydrogen, before stirring was continued for 8 hours at room temperature under a hydrogen134 atmosphere. The reaction mixture was filtered through Celite™ and washed with MeOH (3 x 500 mL). The resulting filtrate was concentrated in vacuo to afford the crude material which was triturated with 10% diethyl ether in n-pentane to afford 2-(3-chloro-5-fluorophenyl)ethan- 1-amine hydrochloride (Intermediate 248) (61.0 g, 94%); 1H NMR (400 MHz, DMSO-d6) δ 8.19 (br s, 3H), 7.38 – 7.18 (m, 3H), 3.09 – 3.03 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H).

[0354] To a stirred solution of 2-(3-chloro-5-fluorophenyl)ethan-1-amine hydrochloride (Intermediate 248) (39.0 g, 186.4 mmol) and triethylamine (129.8 mL, 932.2 mmol) in DCM (600 mL) cooled to 0 °C was added acetyl chloride (19.95 mL, 279.6 mmol) and the resulting reaction mixture was stirred for 30 mins at 0 °C. The reaction mixture was poured into water (500 mL) and extracted into EtOAc (3 x 300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude material which was triturated with n-pentane to afford N-(3-chloro-5- fluorophenethyl)acetamide (Intermediate 249) (35.0 g, 72%). LCMS (Analytical Method M10) tR = 1.82 min, [M+H]+= 216.3 / 218.3.

[0355] A stirred mixture of N-(3-chloro-5-fluorophenethyl)acetamide (Intermediate 249) (35 g, 162.79 mmol) in polyphosphoric acid (350 g, 10% w / w) was heated at 210 °C for 16 hours after which time, the reaction mixture was poured onto ice water (6 L) and the pH adjusted to basic pH by the addition of solid sodium bicarbonate. The reaction mixture was extracted into EtOAc (2 x 2 L) and the combined organic layers were dried over Na2SO4, concentrated in vacuo and the crude material was purified by silica gel chromatography eluting with 1% MeOH in DCM to afford a mixture of 6-chloro-8-fluoro-1-methyl-3,4- dihydroisoquinoline (Intermediate 250) and 8-chloro-6-fluoro-1-methyl-3,4- dihydroisoquinoline (Intermediate 251) (1:1) (28.0 g, 87 %). LCMS (Analytical Method M10) tR = 1.00 min; 1.06 min, [M+H]+= 198.3 / 200.2.

[0356] NB: For some examples it may be possible to separate regioisomers at this stage, which is preferable to final stage separation.

[0357] To an ice cooled, N2 purged solution of a 1:1 mixture of 6-chloro-8-fluoro-1- methyl-3,4-dihydroisoquinoline (Intermediate 250) and 8-chloro-6-fluoro-1-methyl-3,4- dihydroisoquinoline (Intermediate 251) (28.0 g, 142.1 mmol) in MeOH (200 mL) was added sodium borohydride (5.47 g, 213.1 mmol) portion wise and the reaction mixture was allowed to warm to room temperature over 30 mins. The reaction mixture was carefully poured into water (550 mL) and extracted into EtOAc (3 x 300 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (500 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the crude material which was purified by silica gel chromatography eluting with 2% MeOH in DCM to afford mixture of 6-chloro-8-fluoro-1-135 methyl-1,2,3,4-tetrahydroisoquinoline (Intermediate 252) and 8-chloro-6-fluoro-1-methyl- 1,2,3,4-tetrahydroisoquinoline (Intermediate 14) (1:1) (25.0 g, 96%). LCMS (Analytical Method M10) tR= 1.20 min; 1.27 min, [M+H]+= 200.3 / 202.3; 1H NMR (400 MHz, DMSO-d6) δ 7.18 (dd, J= 8.8, 2.4 Hz, 1H), 7.13 (dd, J = 10.0, 2.0 Hz, 1H), 7.04 (s, 1H), 6.98 (dd, J = 11.2, 2.4 Hz, 1H), 4.16 – 4.11 (m, 2H), 3.10 – 2.95 (m, 2H), 2.93 – 2.89 (m, 2H), 2.88 – 2.74 (m, 4H), 1.32 – 1.29 (m, 6H).

[0358] A 25 g mixture of the isomers synthesised according to the above method was separated via Chiral Separation Method C2 and eluted as below:

[0359] Fraction 1: 8-Chloro-6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (Isomer 1) (Intermediate 253): (5.46 g, 21.8 %); LCMS (Analytical Method M10) tR = 0.97 min, [M+H]+= 199.8 / 201.7; HPLC (Analytical Method M11) tR = 7.80 min; 1H NMR (400 MHz, DMSO-d6) δ 7.18 (dd, J = 8.8, 2.8 Hz, 1H), 6.97 (dd, J = 9.2, 2.4 Hz, 1H), 4.11 (q, J = 6.8 Hz, 1H), 3.04 – 3.01 (m, 1H), 2.90 – 2.86 (m, 1H), 2.72 – 2.67 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).

[0360] Fraction 2: 6-Chloro-8-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (Intermediate 252): (9.3 g, 37.2 %); LCMS (Analytical Method M10) tR = 0.98 min, [M+H]+= 199.8 / 201.7; HPLC (Analytical Method M11) tR = 7.97 min; 1H NMR (400 MHz, DMSO-d6) δ 7.15 (dd, J = 10.0, 2.0 Hz, 1H), 7.05 (s, 1H), 4.16 (q, J = 6.8 Hz, 1H), 3.06 – 3.01 (m, 1H), 2.91 – 2.85 (m, 1H), 2.70 – 2.67 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H).

[0361] Fraction 3: 8-Chloro-6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (Isomer 2) (Intermediate 254): (5.54 g, 22.2 %); LCMS (Analytical Method M10) tR = 0.99 min, [M+H]+= 199.8 / 201.7; HPLC (Analytical Method M11) tR = 7.79 min; 1H NMR (400 MHz, DMSO-d6) δ 7.18 (dd, J = 8.8, 2.8 Hz, 1H), 6.97 (dd, J = 9.2, 2.4 Hz, 1H), 4.11 (q, J = 6.8 Hz, 1H), 3.07 – 3.01 (m, 1H), 2.90 – 2.87 (m, 1H), 2.67 – 2.62 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).

[0362] The following intermediates were synthesised according to the above methods from commercially available phenethylamines.titIMethod M2)136 tR = 0.40 + ) + 1 ) 1 + 0 ) 1 + 2 t ) 1 + 1Method M5)137 tR = 0.62 + 2 2 2 2 20.957 min,138 [M+H]+=

[0363] The following chiral intermediates were produced by separating commercially available tetrahydroisoquinolines or terahydroisoquinolines synthesised according to Intermediate route 4 using Chiral Separation Method C1 (1S)-68-dichloro-1-methyl- R RIntermediate route 5 exemplified by the synthesis of S)-6-chloro-1-methyl-1,2,3,4- tetrahydroisoquinoline (Intermediate 15)

[0364] A solution of (1S)-1-(4-chlorophenyl)ethanamine (10.0 g, 64.3 mmol) in toluene (50 mL) was treated with 2-bromoethanol (5.0 mL, 70.7 mmol) with stirring at 100 °C for 16 hours. The reaction mixture was cooled and concentrated and the solid was diluted with water (60 mL), acidified to pH 1 using 1 M HCl and washed with diethyl ether (2 x 20 mL). The aqueous was basified to pH 10 by addition of saturated sodium carbonate and extracted into DCM (5 x 20 mL). The combined organics were dried over MgSO4, filtered and concentrated to give 2-[[(1S)-1-(4-chlorophenyl)ethyl]amino]ethanol (Intermediate 157) as a red / orange oil which was used directly without additional purification (13.72 g, 63.9 mmol, quant). LCMS (Analytical Method M2) tR = 0.44 min, [M+H]+= 200.2 / 202.1; 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.23 (m, 4H), 3.80 (q, J = 6.6 Hz, 1H), 3.68 – 3.52 (m, 2H), 2.75 – 2.55 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H), NH and OH not observed.

[0365] A solution of 2-[[(1S)-1-(4-chlorophenyl)ethyl]amino]ethanol (Intermediate 157) (13.72 g, 63.9 mmol) and hydrogen bromide (48%, 36 mL, 0.320 mol) was stirred at 140 °C for 16 hours. The reaction mixture was cooled, the solid was concentrated in vacuo and triturated in acetone (30 mL). The heavily precipitated solution was filtered in vacuo and the beige solid was rinsed with acetone (10 mL). The solid was further rinsed with diethyl ether (20 mL), collected and dried to afford (1S)-N-(2-bromoethyl)-1-(4- chlorophenyl)ethanamine hydrobromide (Intermediate 158) as a beige solid (7.43 g, 27%).139 LCMS (Analytical Method M2) tR= 0.54 min, [M+H]+= 262.0 / 264.0; 1H NMR (400 MHz, DMSO-d6) δ 9.43 – 8.87 (m, 2H), 7.56 (s, 4H), 4.61 – 4.42 (m, 1H), 3.64 (t, J = 6.7 Hz, 2H), 3.18 – 3.02 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H), NH not observed.

[0366] To a stirred suspension of (1S)-N-(2-bromoethyl)-1-(4- chlorophenyl)ethanamine hydrobromide (Intermediate 158) (12.73 g, 33.4 mmol) in decalin (100 mL, 33.4 mmol) at 130 °C was added aluminium trichloride (7.12 g, 53.4 mmol) and stirring continued for 16 hours. Aluminium trichloride (4.45 g, 33.4 mmol) was added and stirring continued at 130 °C for a further 48 hours. The reaction mixture was cooled to room temperature and the decalin was decanted. The remaining viscous oil was added to water (200 mL) at 0 °C and triturated to dissolve most of the solid. Diethyl ether (100 mL) was added and the mixture was sonicated to fully dissolve any solid giving a biphasic mixture. The diethyl ether was separated and the aqueous washed further with diethyl ether (3 x 20 mL). The aqueous was basified to pH 14 by addition of solid sodium hydroxide at 0 °C and was extracted into DCM (5 x 30 mL). The combined organics were dried over MgSO4, filtered and concentrated to give an orange oily solid (Intermediate 15) (5.30 g, 54%). LCMS (Analytical Method M5) tR = 0.65 min, [M+H]+= 182.1 / 184.1; 1H NMR (500 MHz, CDCl3) δ 7.10 (dd, J = 8.3, 2.2 Hz, 1H), 7.07 – 7.00 (m, 2H), 4.15 (q, J = 6.6 Hz, 1H), 3.28 (dt, J = 12.5, 5.3 Hz, 1H), 3.08 – 3.00 (m, 1H), 2.94 – 2.86 (m, 1H), 2.77 (dt, J = 16.7, 5.0 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H). Intermediate route 5 exemplified by the synthesis of (1S)-6-fluoro-1-methyl-1,2,3,4- tetrahydroisoquinoline (Intermediate 274)

[0367] To a stirred solution of (1S)-1-(4-fluorophenyl)ethanamine (22.00 g, 158.2 mmol) in DMF (30 mL) cooled to 0 °C was added sodium hydride (12.66 g, 60%, 316.5 mmol) followed by 2-bromoethan-1-ol (39.56 g, 316.5 mmol) and the mixture was heated to 130 °C for 4 hours. The reaction mixture was cooled and poured into water (200 mL) and extracted into EtOAc (3 x 150 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give 2-[[(1S)-1-(4-fluorophenyl)ethyl]amino]ethanol (Intermediate 298) which was used directly without additional purification (20.0 g, 69%). LCMS (Analytical Method M10) tR = 0.98 min, [M+H]+= 184.3; 1H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.33 (m, 2H), 7.16 – 7.09 (m, 2H), 4.44 (t, J = 5.2 Hz, 1H), 3.73 – 3.68 (m, 1H), 3.42 – 3.36 (m, 2H), 2.52 – 2.29 (m, 2H), 1.22 (d, J= 6.4 Hz, 3H), OH not observed.

[0368] A solution of 2-[[(1S)-1-(4-fluorophenyl)ethyl]amino]ethanol (Intermediate140 298) (20.0 g, 109.2 mmol) and hydrogen bromide (63%, 80 mL, 4 vol) was stirred at 120 °C for 16 hours. The reaction mixture was cooled and the solid was concentrated in vacuo and triturated in acetone (200 mL). The heavily precipitated solution was filtered under vacuum to afford (1S)-N-(2-bromoethyl)-1-(4-fluorophenyl)ethanamine hydrobromide (Intermediate 299) (16.0 g, 44%). LCMS (Analytical Method M10) tR = 1.16 min, [M+H]+= 246.2 / 248.1; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (bs, 1H), 9.09 (bs, 1H), 7.63 – 7.60 (m, 2H), 7.32 (t, J = 8.8 Hz, 2H), 4.53 (q, J = 6.8, 12.0 Hz, 1H), 3.71 – 3.62 (m, 2H), 3.52 – 3.49 (m, 2H), 1.59 (d, J = 7.2 Hz, 3H).

[0369] To a stirred solution of (S)-2-bromo-N-(1-(4-fluorophenyl)ethyl)ethan-1-amine hydrobromide (8.0 g, 24.6 mmol) (Intermediate 299) in decalin (80 mL) at 140 °C was added aluminium trichloride (26.19 g, 196.9 mmol) and stirring continued for 48 hours. The reaction mixture was poured into water (200 mL) and extracted into diethyl ether (3 x 150 mL) to remove any impurities. The aqueous was basified to pH 10 by addition of aqueous NaOH (80 mL) and extracted into DCM (3 x 150 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 4% MeOH in DCM to afford (1S)-6-fluoro-1-methyl-1,2,3,4- tetrahydroisoquinoline (Intermediate 274) (4.0 g, 49.5%); LCMS (Analytical Method M10) tR = 0.97 min, [M+H]+= 166.3; 1H NMR (400 MHz, DMSO-d6) δ 7.27 – 7.22 (m, 1H), 7.04 – 6.97 (m, 2H), 4.18 (q, J = 6.4, 13.2 Hz, 1H), 3.24 – 3.16 (m, 1H), 3.04 – 2.98 (m, 1H), 2.93 – 2.85 (m, 1H), 2.81 – 2.75 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), NH not observed.

[0370] The following intermediates were synthesised according to the above methods from commercially available starting materials. .141 LCMS (AnalyticalIntermediate route 6 exemplified by the synthesis of 1,1,6-trimethyl-3,4-dihydro-2H- isoquinoline (Intermediate 17)

[0371] A solution of N-[2-(m-tolyl)ethyl]acetamide (2.80 g, 14.7 mmol) in polyphosphoric acid (10 mL, 73.5 mmol) was stirred at 130 °C for 16 hours. The reaction mixture was slowly added to a stirred solution of ice water (150 mL). Aqueous ammonia (35%) was added to the stirring solution until the pH reached 9 –10 and the resulting opaque aqueous was extracted into DCM (5 x 40 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford 1,6-dimethyl-3,4-dihydroisoquinoline (Intermediate 159) as a brown oil (2.65 g, 93%). LCMS (Analytical Method M5) tR = 0.64 min, [M+H]+= 160.1; 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 3.70 – 3.62 (m, 2H), 2.72 – 2.64 (m, 2H), 2.39 (s, 3H), 2.37 (s, 3H).

[0372] 1,6-Dimethyl-3,4-dihydroisoquinoline (0.65 g, 3.35 mmol) and (bromomethyl)benzene (0.48 mL, 4.02 mmol) in toluene (6 mL) were heated to 90 °C for 6 hours after which time the reaction mixture was cooled and the excess toluene decanted to leave a brown, viscous oil which was concentrated in vacuo and used directly in the following step (Intermediate 160). LCMS (Analytical Method M5) tR = 0.69 min, [M+H]+= 250.2.

[0373] To a stirred solution of 2-benzyl-1,6-dimethyl-3,4-dihydroisoquinolin-2-ium bromide (Intermediate 160) (1.53 g, 1.76 mmol) in DCM (15 mL) at 0 °C was added bromo(methyl)magnesium (3.5 mL of 3 M in Et2O, 10.6 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours after which time the reaction mixture was cooled to 0 °C and quenched by addition of water (20 mL). The142 suspension was concentrated and then extracted into Et2O (3 x 10 mL), the combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a brown oil which was purified by silica gel chromatography eluting with 1 – 64% EtOAc in heptane to afford 2-benzyl-1,1,6-trimethyl-3,4-dihydroisoquinoline (Intermediate 161) as a yellow oil (0.59 g, 1.75 mmol, quantitative). LCMS (Analytical Method M5) tR = 1.15 min, [M+H]+= 266.3.

[0374] A stirred solution of 2-benzyl-1,1,6-trimethyl-3,4-dihydroisoquinoline (0.59 g, 1.76 mmol) in EtOH (10 mL) at room temperature was placed under N2, treated with 10% palladium on carbon (187 mg, 0.176 mmol) and placed under a hydrogen atmosphere and stirred at room temperature for 64 hours. The reaction mixture was filtered through a pad of Celite™ and the filtrate was concentrated to afford 1,1,6-trimethyl-3,4-dihydro-2H- isoquinoline (Intermediate 17) as a cloudy grey oil (337 mg, 50%). LCMS (Analytical Method M2) tR = 0.50 min, [M+H]+= 176.1; 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.12 (m, 1H), 6.94 – 6.88 (m, 1H), 6.85 – 6.79 (m, 1H), 3.06 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.22 (d, J = 4.1 Hz, 3H), 1.38 (s, 6H), NH not observed. Intermediate route 7 exemplified by the synthesis of 2‐[(7‐fluoro‐1‐oxo‐1,2‐dihydroisoquinolin‐6‐yl)amino]acetic acid (Intermediate 11)

[0375] A mixture of tert-butyl glycinate (283 mg, 2.16 mmol), 6-bromo-7-fluoro-2H- isoquinolin-1-one (500 mg, 2.07 mmol) and caesium carbonate (1344 mg, 4.13 mmol) in tert- butanol (12 mL) was degassed for 5 mins before the reaction mixture was charged with BrettPhos Pd G3 (189 mg, 0.208 mmol) and the reaction mixture was further degassed briefly before being heated at 100 °C for 16 hours. The reaction mixture was separated between DCM and water and passed through a phase separator. The solvents were removed in vacuo and the crude material was purified by high pH reverse phase chromatography eluting with 10 – 40% 0.1% ammonia in MeCN in 0.1% ammonia in water to yield the desired product, tert-butyl 2-[(7-fluoro-1-oxo-2H-isoquinolin-6-yl)amino]acetate (Intermediate 151) (610 mg, 76%), as a light brown powder. LCMS (Analytical Method M2) tR = 0.73 min, [M+H]+= 293.2; 1H NMR (400 MHz, DMSO-d6) δ 10.98 – 10.80 (m, 1H), 7.65 (d, J = 12.4 Hz, 1H), 7.04 – 6.98 (m, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.57 – 6.50 (m, 1H), 6.32 (d, J = 7.1 Hz, 1H), 3.94 (d, J = 6.4 Hz, 2H), 1.42 (s, 9H).

[0376] TFA (0.40 mL, 5.22 mmol) was added to a stirred solution of tert-butyl 2-[(7-143 fluoro-1-oxo-2H-isoquinolin-6-yl)amino]acetate (Intermediate 151) (75 mg, 0.257 mmol) in DCM (3 mL), and the reaction mixture was left to stir at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to give 2-[(7-fluoro-1-oxo-2H-isoquinolin-6- yl)amino]acetic acid (Intermediate 11) (76 mg, 99%) as a white solid. LCMS (Analytical Method M2) tR = 0.41 min, [M+H]+= 237.2; 1H NMR (500 MHz, DMSO-d6) δ 10.90 (d, J = 4.3 Hz, 1H), 7.66 (d, J = 12.4 Hz, 1H), 7.07 – 6.85 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.1 Hz, 1H), 3.97 (s, 2H), NH and acidic OH not observed. Intermediate route 8 exemplified by the synthesis of 2-[(6-fluoro-4-oxo-3H-quinazolin-7- yl)amino]acetic acid (Intermediate 10)

[0377] A solution of 6,7-difluoro-3H-quinazolin-4-one (3.14 g, 14.5 mmol), tert-butyl glycinate hydrochloride (22.67 g, 15.9 mmol) and DIPEA (7.6 mL, 43.4 mmol) in NMP (20 mL) was stirred at 120 °C for 72 hours. The reaction mixture was cooled and poured into water (300 mL). Saturated sodium bicarbonate (50 mL) was added to the aqueous phase and the solution was extracted into EtOAc (5 x 100 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and concentrated to afford a beige paste which was purified by silica gel chromatography eluting with 25 – 100% EtOAc in heptane followed by 0 – 24% MeOH in EtOAc to afford tert-butyl 2-[(6-fluoro-4-oxo-3H- quinazolin-7-yl)amino]acetate (Intermediate 152) (0.90 g, 19%). LCMS (Analytical Method M5) tR= 0.60 min, [M+H]+= 294.2; 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 11.8 Hz, 1H), 6.83 – 6.77 (m, 1H), 6.62 (d, J = 8.0 Hz, 1H), 3.97 (d, J = 6.3 Hz, 2H), 1.42 (s, 9H).

[0378] tert-Butyl 2-[(6-fluoro-4-oxo-3H-quinazolin-7-yl)amino]acetate (Intermediate 152) (1.19 g, 2.64 mmol) was dissolved in DCM (5 mL). TFA (5 mL) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene to afford 2-[(6-fluoro-4-oxo-3H- quinazolin-7-yl)amino]acetic acid (Intermediate 10) (1.50 g, 84%) as a white solid. LCMS (Analytical Method M2) tR = 0.34 min, [M+H]+= 238.0. Intermediate route 9 exemplified by the synthesis of 2-amino-7-bromo-3H-quinazolin-4-one (Intermediate 18)144

[0379] To a solution of 7-bromo-2,4-dichloroquinazoline (250 mg, 0.900 mmol) in THF (2 mL) was added sodium hydroxide in water (2.0 mL, 9.28 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 10% AcOH (5 mL) and the aqueous mixture was extracted into EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography eluting with 3 – 15 % MeOH in DCM to give 7-bromo-2-chloro-3H- quinazolin-4-one (Intermediate 162) (165 mg, 71%) as a yellow solid. LCMS (Analytical Method M03) tR= 3.54 min, [M+H]+= 258.8 / 260.8; 1H NMR (500 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.72 (dd, J = 8.5, 1.9 Hz, 1H).

[0380] To a solution of 7-bromo-2-chloro-3H-quinazolin-4-one (40 mg, 0.154 mmol) in MeOH (0.4 mL) was added ammonia (7 N in MeOH, 0.4 mL) and DIPEA (0.040 mL, 0.229 mmol) and the reaction mixture was heated to 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo and the crude material was purified by silica gel chromatography eluting with 5 – 10 % MeOH in DCM to give the desired product 2-amino-7-bromo-3H-quinazolin-4-one (Intermediate 18) (25 mg, 68%) as a white solid. LCMS (Analytical Method M01) tR = 0.75 min, [M+H]+= 239.9 / 241.9; 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.23 (dd, J = 8.4, 1.8 Hz, 1H), 6.57 (s, 2H).

[0381] The following intermediates were synthesised either partially or wholly according to the above method. . Intermediate route 10 exemplified by the synthesis of 6,8-difluoro-1-methyl-1,2,3,4- tetrahydroisoquinoline (Intermediate 20)145

[0382] A stirred solution of 2-phenylethanamine (2.0 mL, 15.9 mmol), ethyl difluoroacetate (1.8 mL, 16.7 mmol) and triethylamine (2.1 mL, 15.9 mmol) in DCM (32 mL) was stirred under N2 at 45 °C for 16 hours. The reaction mixture was washed with water (3 x 15 mL) and dried over MgSO4 to yield 2,2-difluoro-N-(2-phenylethyl)acetamide (Intermediate 163) as a pale yellow oil (3.16 g, 96%). LCMS (Analytical Method M5) tR = 0.58 min, [M+H]+= 198.3; 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.31 (m, 2H), 7.28 – 7.24 (m, 1H), 7.21 – 7.17 (m, 2H), 6.31 (s, 1H), 5.86 (t, J = 54.3 Hz, 1H), 3.61 (q, J = 6.9 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H).

[0383] A solution of 2,2-difluoro-N-(2-phenylethyl)acetamide (Intermediate 163) (3.29 g, 15.9 mmol) in PPA (11 mL, 79.3 mmol) was stirred under N2 at 170 °C for 16 hours. The reaction mixture was slowly decanted into a stirred solution of water (100 mL) at 0 °C. Aqueous ammonia (35%) was added to the stirring solution until the pH had reached 9-10. The resulting aqueous was extracted into DCM (5 x 30 mL) and the combined organics were dried over MgSO4, filtered and concentrated to afford 1-(difluoromethyl)-3,4- dihydroisoquinoline as a brown oil (Intermediate 164) (2.12 g, 72%). LCMS (Analytical Method M5) tR = 0.67 min, [M+H]+= 182.1; 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.74 (m, 1H), 7.42 (td, J = 7.5, 1.2 Hz, 1H), 7.36 – 7.30 (m, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.28 (t, J = 54.6 Hz, 1H), 3.83 (ddt, J = 7.7, 6.1, 3.1 Hz, 2H), 2.81 – 2.68 (m, 2H).

[0384] To a stirred solution of 1-(difluoromethyl)-3,4-dihydroisoquinoline (1.00 g, 5.41 mmol) in MeOH (35 mL) at 0 °C was added sodium borohydride (532 mg, 14.06 mmol). The reaction was stirred at room temperature for 90 mins, and the reaction mixture was quenched with water (5 mL) and the solution was concentrated to remove MeOH. The aqueous was diluted by addition of saturated sodium bicarbonate, extracted into DCM (4 x 10 mL) and the combined organics were dried over MgSO4, filtered and concentrated to give 6,8-difluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (Intermediate 20) as a brown oil (0.88 g, 77%). LCMS (Analytical Method M2) tR= 0.60 min, [M+H]+= 184.1; 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.26 (m, 1H), 7.25 – 7.17 (m, 2H), 7.18 – 7.13 (m, 1H), 5.86 (td, J = 56.5, 4.9 Hz, 1H), 4.23 (td, J = 12.3, 4.8 Hz, 1H), 3.25 (dt, J = 12.1, 6.1 Hz, 1H), 3.06 (dt, J = 11.8, 5.6 Hz, 1H), 2.84 (t, J = 5.8 Hz, 2H), NH not observed. Intermediate route 11 exemplified by the synthesis of 6-bromo-4,7-difluoro-2H-isoquinolin-1- one (Intermediate 21)146

[0385] To a stirred solution of 6-bromo-7-fluoro-2H-isoquinolin-1-one (100 mg, 0.413 mmol) in MeOH:MeCN (2 mL, 1:1, v:v) was added 1-(chloromethyl)-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane ditetrafluoroborate (155 mg, 0.438 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, re-dissolved in DCM (1 mL) and heated with 1 M HCl (1 mL) at 50 °C for 16 hours before being partitioned between EtOAc (10 mL) and saturated sodium bicarbonate (10 mL). The aqueous was re-extracted into EtOAc (10 mL) and the combined organics washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to give the crude as an orange oil which was precipitated with DCM (1 mL) to afford 6-bromo-4,7- difluoro-3-hydroxy-3,4-dihydro-2H-isoquinolin-1-one as a mixture of diastereomers. Methanesulfonic acid (0.20 mL, 3.08 mmol) was added to a suspension of 6-bromo-4,7- difluoro-3-hydroxy-3,4-dihydro-2H-isoquinolin-1-one in DCM (1 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between a solution of IPA:CHCl3 (5 mL, 3:1, v:v) and a saturated solution of sodium bicarbonate (5 mL). The layers were separated and the aqueous further extracted with IPA:CHCl3 (10 mL). The organic layers were combined and washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product, 6-bromo-4,7-difluoro-2H-isoquinolin- 1-one (Intermediate 21) (70 mg, 0.256 mmol, 62%) as an off-white solid. LCMS (Analytical Method M3) tR = 1.02 min, [M+H]+= 259.9 / 261.9; 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 8.01 (dd, J = 9.0, 1.9 Hz, 1H), 7.46 (d, J = 6.0 Hz, 1H). Intermediate route 12 exemplified by the synthesis of 2-bromo-4-[[2-(6,8-dichloro-1-methyl- 3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-5-fluoro-benzonitrile (Intermediate 22)

[0386] To a solution of 2-bromo-4,5-difluorobenzonitrile (2.00 g, 9.17 mmol) in DMSO (30 mL) was added tert-butyl glycinate hydrochloride (1.69 g, 10.1 mmol) and147 potassium carbonate (3.80 g, 27.5 mmol) and the solution was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted into EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting in 0 – 50% EtOAc in heptane to give tert-butyl 2-(5-bromo-4-cyano- 2-fluoro-anilino)acetate (Intermediate 91) (2.40 g, 76%) as an orange solid. LCMS (Analytical Method M1) tR= 1.22 min, [M+H]+= 328.9 / 330.9; 1H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J = 11.8 Hz, 1H), 7.15 – 7.06 (m, 1H), 6.99 (d, J = 7.9 Hz, 1H), 4.00 (d, J = 6.4 Hz, 2H), 1.42 (s, 9H).

[0387] tert-Butyl 2-(5-bromo-4-cyano-2-fluoro-anilino)acetate (Intermediate 91) (2.40 g, 7.29 mmol) was dissolved in DCM:TFA (40 mL, 3:1, v:v) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give 2-(5-bromo-4-cyano-2-fluoro-anilino)acetic acid (Intermediate 92) (2.10 g, 95%) as an orange foam. LCMS (Analytical Method M1) tR = 0.98 min, [M+H]+= 272.9 / 274.9.

[0388] To a stirred solution of 2-(5-bromo-4-cyano-2-fluoro-anilino)acetic acid (Intermediate 92) (1.00 g, 3.30 mmol), 6,8-dichloro-1-methyl-1,2,3,4-tetrahydroisoquinoline (712 mg, 3.30 mmol) and DIPEA (1.2 mL, 6.59 mmol) in DMF (22.5 mL) was added HATU (1.88 g, 4.94 mmol) and the reaction mixture was stirred at room temperature for 2 hours before diluting with EtOAc (20 mL). The mixture was washed with water (3 x 10 mL), brine (10 mL) and the organic fraction was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 – 60% EtOAc in heptane to afford 2-bromo-4-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-5-fluoro-benzonitrile (Intermediate 22) (1.55 g, 90%) as an off white solid. LCMS (Analytical Method M1) tR = 1.39 min, [M+H]+= 471.8; 1H NMR (400 MHz, DMSO-d6) δ 7.75 – 7.65 (m, 1H), 7.55 – 7.46 (m, 1H), 7.42 – 7.30 (m, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.67 – 6.53 (m, 1H), 5.71 – 5.10 (m, 1H), 4.31 – 4.11 (m, 2H), 3.91 – 3.62 (m, 2H), 3.09 – 2.88 (m, 2H), 1.59 – 1.35 (m, 3H).dihydro-1H-isoquinolin-2-436.1 / 438.1148 yl]-2-oxo-ethyl]amino]-5- ) )Intermediate route 13 exemplified by the synthesis of 2‐[(6‐fluoro‐2‐methyl‐4‐oxo‐3,4‐dihydroquinazolin‐7‐yl)amino]acetic acid (Intermediate 23)

[0389] To a suspension of tert-butyl 2-(5-bromo-4-cyano-2-fluoro-anilino)acetate (160 mg, 0.437 mmol), acetamide (28 mg, 0.481 mmol), caesium carbonate (143 mg, 0.437 mmol) and XantPhos (13 mg, 0.0219 mmol) in 1,4-dioxane (4 mL) sparged with N2for 2 mins was added Pd2(dba)3(20 mg, 0.0219 mmol) and the reaction mixture was heated to 70 °C for 6 hours. The reaction mixture was cooled and left standing at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (3 mL) and filtered through cotton wool. The filtrate was concentrated to a yellow oil and the crude material was purified by silica gel chromatography eluting with 10 – 78% EtOAc in heptane to afford tert-butyl 2-(5-acetamido- 4-cyano-2-fluoro-anilino)acetate (Intermediate 266) (140 mg, 97%) as a pale yellow solid. LCMS (Analytical Method M5) tR= 0.68 min, [M+H]+= 306.3; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.18 – 7.09 (m, 1H), 5.15 (s, 1H), 3.91 (s, 2H), 2.26 (s, 3H), 1.53 (s, 9H).

[0390] To a solution of tert-butyl 2-(5-acetamido-4-cyano-2-fluoro-anilino)acetate (Intermediate 266) (3.44 g, 9.40 mmol) in 1,4-dioxane:water (60 mL, 2:1 v:v) was added 4149 M HCl in 1,4-dioxane (25 mL) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was basified to pH 14 using 5 M NaOH (~25 mL) and stirring was continued for a further 2 hours. The reaction mixture was concentrated to remove 1,4- dioxane and the remaining aqueous was washed with diethyl ether (50 mL). The aqueous was acidified to pH 2 using 3 M HCl, the precipitate was filtered and the solid collected, the filtrate was concentrated to 1 / 3 of the volume and cooled to 0 °C. The resulting precipitate was filtered and both solid product crops were combined and left to dry overnight to afford 2- [(6-fluoro-2-methyl-4-oxo-3H-quinazolin-7-yl)amino]acetic acid (Intermediate 23) (2.26 g, 81%) as a beige solid. LCMS (Analytical Method M2) tR = 0.33 min, [M+H]+= 252.4; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 12.08 (s, 1H), 7.57 (d, J = 11.7 Hz, 1H), 6.78 (s, 1H), 6.55 (d, J = 7.9 Hz, 1H), 3.98 (d, J = 5.6 Hz, 2H), 2.30 (d, J = 9.5 Hz, 3H). Intermediate route 13 exemplified by the synthesis of N-[2-cyano-5-[[2-(6,8-dichloro-1- methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-4-fluoro-phenyl]-2-hydroxy- acetamide (Intermediate 232)

[0391] To a N2sparged solution of 2-bromo-4-[[2-(6,8-dichloro-1-methyl-3,4-dihydro- 1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-5-fluoro-benzonitrile (Intermediate 22) (100 mg, 0.212 mmol), 2-hydroxyacetamide (16 mg, 0.212 mmol) and caesium carbonate (69 mg, 0.212 mmol) in 1,4-dioxane (2.8 mL) was added Pd2(dba)3(10 mg, 0.0106 mmol) and XantPhos (6.1 mg, 0.0106 mmol) and the solution was degassed for a further 5 mins before heating to 100 °C for 12 hours. The reaction mixture was diluted with DCM (10 mL), filtered through a phase separator and the filtrate was washed with saturated sodium bicarbonate solution (5 mL) and brine (5 mL). The organic extract was dried over Na2SO4, filtered and concentrated in vacuo to yield the crude product which was purified by silica gel chromatography (Amino Duo column) eluting in 0 – 100% EtOAc in heptanes to give N-[2- cyano-5-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-4- fluoro-phenyl]-2-hydroxy-acetamide (Intermediate 232) (51 mg, 51%) as a white solid. LCMS (Analytical Method M1) tR= 1.17 min, [M+H]+= 464.9 / 466.9; 1H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.59 – 7.53 (m, 1H), 7.53 – 7.48 (m, 1H), 7.41 – 7.32 (m, 1H), 7.21 – 7.11 (m, 1H), 6.57 – 6.42 (m, 1H), 5.99 (s, 1H), 5.74 – 5.07 (m, 1H), 4.28 – 4.09 (m, 2H), 4.01 – 3.97 (m, 2H), 3.92 – 3.79 (m, 1H), 3.73 – 3.65 (m, 1H), 3.09 – 2.76 (m, 2H), 1.59 – 1.33 (m, 3H).150

[0392] Examples synthesised using this Intermediate route were completed according to General Method 10 t- -carboxyate151 tert-butyl (2S)-2-[[2-cyano-5-]carbamate152 tert-butyl 2-[2-[2-cyano-5-[[2-methyl-propyl]carbamate153 tert-butyl N-[(1S)-2-[2-cyano-butyl]carbamate154 N-[5-[[2-[(1S)-6-chloro-1- Clethyl]carbamate155 N-[2-cyano-5-[[2-(6,8-dicarboxylate156 tert-butyl N-[2-[5-[[2-[(1S)-6-carboxylate157 tert-butyl (3S)-3-[2-[5-[[2- N Cl Fpopy e y ca a ae158 tert-butyl (3R)-3-[2-[2-cyano- N Cl FIntermediate route 14 exemplified by the synthesis of 1-methyl-1,2,3,4- tetrahydroisoquinoline-6-carbonitrile trifluoroacetate salt (Intermediate 24)

[0393] To a solution of 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (Intermediate 13) (200 mg, 0.885 mmol) and DIPEA (0.46 mL, 2.65 mmol) in DCM (5 mL) was added BOC anhydride (232 mg, 1.06 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (10 mL) and washed with 2 M sodium hydroxide (10 mL) and water (10 mL). The organics were dried over MgSO4, filtered, concentrated to an orange oil and purified by silica gel chromatography eluting with 0 – 30% EtOAc in heptane to afford tert-butyl 6-bromo-1-methyl-3,4-dihydro-1H- isoquinoline-2-carboxylate (Intermediate 165) as a colourless oil (308 mg, 94%). LCMS (Analytical Method M5) tR = 1.02 min, [M-Boc+MeCN+H]+= 311.1 / 313.2; 1H NMR (400 MHz,159 CDCl3) δ 7.29 (d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 5.30 – 4.97 (m, 1H), 4.28 – 3.87 (m, 1H), 3.15 (s, 1H), 2.96 – 2.77 (m, 1H), 2.73 – 2.56 (m, 1H), 1.49 (s, 9H), 1.41 (d, J = 6.8 Hz, 3H).

[0394] A solution of tert-butyl 6-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2- carboxylate (Intermediate 165) (175 mg, 0.472 mmol) and zinc cyanide (67 mg, 0.566 mmol) in DMA (2.5 mL) was sparged with N2for 5 mins then tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.0472 mmol) was added and the reaction mixture was heated to 100 °C for 3 hours. The reaction mixture was cooled, diluted with saturated sodium bicarbonate (15 mL) and extracted into EtOAc (3 x 5 mL). The combined organics were washed with brine (3 x 10 mL), dried over MgSO4, filtered, concentrated and the crude material was purified by silica gel chromatography eluting 0 – 40% EtOAc in heptane to afford tert-butyl 6-cyano-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (Intermediate 166) as a colourless oil. (19 mg, 13%). LCMS (Analytical Method M5) tR = 0.84 min, [M-Boc+MeCN+H]+= 258.2.

[0395] A solution of tert-butyl 6-cyano-1-methyl-3,4-dihydro-1H-isoquinoline-2- carboxylate (Intermediate 166) (19 mg, 0.0593 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 2 hours and the reaction mixture was concentrated to give 1- methyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile trifluoroacetate salt (Intermediate 24) as a grey waxy solid (22 mg, quant). LCMS (Analytical Method M5) tR = 0.5 min, [M+H]+= 173.1. Intermediate route 15 exemplified by the synthesis of tert-butyl 1-methyl-6-phenyl-3,4- dihydro-1H-isoquinoline-2-carboxylate (Intermediate 26)

[0396] To a solution of tert-butyl 6-bromo-1-methyl-3,4-dihydro-1H-isoquinoline-2- carboxylate (Intermediate 165) (175 mg, 0.472 mmol), phenylboronic acid (63 mg, 0.519 mmol) and potassium carbonate (130 mg, 0.944 mmol) in toluene:EtOH (2 mL; 3:1 v:v) sparged with N2for 5 mins was added palladium tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.0236 mmol) and the reaction mixture was stirred at 100 °C under microwave irradiation for 1.5 hours. The reaction mixture was diluted with water (10 mL) and saturated sodium bicarbonate (10 mL) and extracted into EtOAc (15 mL) The organic layer was separated and washed with brine (2 x 10 mL), dried over MgSO4, filtered and concentrated to give the crude product as a pale yellow solid which was purified by silica gel160 chromatography eluting with 0 – 31% EtOAc in heptane to afford tert-butyl 1-methyl-6- phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (Intermediate 267) as a colourless oil (91 mg, 36%). LCMS (Analytical Method M5) tR= 1.05 min, [M+H]+= 309.3; 1H NMR (500 MHz, CDCl3) δ 7.53 – 7.47 (m, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.21 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.2 Hz, 2H), 5.18 – 4.93 (m, 1H), 4.20 – 3.85 (m, 1H), 3.25 – 3.00 (m, 1H), 2.94 – 2.58 (m, 2H), 1.42 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H).

[0397] BOC deprotection of Intermediate 267 is carried out according to General Method 6 or General Method 7 or according to the method detailed in Intermediate route 16. Intermediate route 16 exemplified by the synthesis of 1-methyl-6-(1,2-oxazol-4-yl)-1,2,3,4- tetrahydroisoquinoline (Intermediate 28)

[0398] To a N2 sparged solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2-oxazole (34 mg, 0.173 mmol), tert-butyl 6-bromo-1-methyl-3,4-dihydro-1H-isoquinoline- 2-carboxylate (Intermediate 165) (50 mg, 0.144 mmol) and potassium fluoride (25 mg, 0.432 mmol) in DMSO:water (400 µL, 3:1; v:v) was added Pd(dppf)Cl2 (21 mg, 0.0288 mmol) and the reaction mixture was heated to 70 °C for 1.5 hours. The reaction mixture was cooled, diluted with water (10 mL) and extracted into EtOAc (2 x 5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to yield the crude product which was purified by silica gel chromatography eluting with 12 – 100% EtOAc in heptane to afford tert-butyl 6-isoxazol-4-yl-1-methyl-3,4-dihydro-1H- isoquinoline-2-carboxylate (Intermediate 167) (26 mg, 40%) as a yellow oil. LCMS (Analytical Method M5) tR = 0.56 min, [M-H]- = 313.3.

[0399] A solution of tert-butyl 6-isoxazol-4-yl-1-methyl-3,4-dihydro-1H-isoquinoline-2- carboxyla...

Claims

359 P360887GB1 CLAIMS 1. A compound according to Formula (I) or (II) below, or a pharmaceutically acceptable salt thereof: 510 RT is selected from hydrogen or fluoro; RV is selected from hydrogen or methyl; W is selected from CRW and N; X is selected from CRX and N; Y is selected from CRY and N; 15 Z is selected from CRZ and N; with the proviso that only one of W and X can be N, and only one of Y and Z can be N;360 P360887GB1 wherein RWand RXare independently selected from hydrogen, halo, methyl, cyano or a group RA; with the proviso that when W is CRWand X is CRX, then at least one of RWand RXis selected from hydrogen, halo, methyl or cyano; wherein RAis a group of the formula: 5 XA-YA-ZAwherein XAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, halo, ORX1, NRX1RX2, C3-6cycloalkyl or (1-2C)alkyl, wherein RX1and RX2are independently 10 selected from hydrogen or methyl;or RXaand RXbcan be linked such that, together with the carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; YAis absent or selected from -O-, -S-, -S(O)-, -S(O)2- -C(O)-, -C(O)O-, -OC(O)-, - CH(ORY1)-, -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; 15 ZAis selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, C3- 12cycloalkyl, aryl (e.g. phenyl), heterocyclyl or heteroaryl; and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- alkyl, halo, (1-6C)haloalkyl, heterocyclyl, heteroaryl, aryl, C3-8cycloalkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl, aryl(1-2C)alkyl, C3-8cycloalkyl(1-2C)- 20 alkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2or S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; and any (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, 25 heteroaryl(1-2C)alkyl or aryl(1-2C)alkyl, in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, ORZ3, NRZ3RZ4, S(O)0-2RZ3or methyl; wherein RZ3and RZ4are each independently selected from hydrogen or (1- 2C)alkyl; RXNis selected from hydrogen, (1-6C)alkyl, heterocyclyl or C3-8cycloalkyl, each of which 30 being optionally substituted by one or more substituents selected from halo, (1-6C)haloalkyl, (1-6C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3, C(O)ORZ3, OC(O)RZ3, C(O)N(RZ3)RZ4, N(RZ3)C(O)RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or (1- 2C)alkyl;361 P360887GB1 RYis selected from hydrogen, halo, NH2, cyano, or (1-2C)alkyl optionally substituted with NH2, hydroxy or cyano; RZis selected from hydrogen, halo, NH2, cyano, or (1-2C)alkyl optionally substituted with NH2, hydroxy or cyano, 5 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; R5 and R7 are each independently selected from hydrogen, halo, hydroxy, methyl or methoxy; 10 R6 and R8 are each independently selected from hydrogen, hydroxy, cyano, amino, (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, aryl or heteroaryl; wherein any (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, aryl or heteroaryl is optionally substituted with one or more of hydroxy, cyano, NH2, oxo, (1-4C)alkyl, halo, (1- 4C)haloalkyl or (1-4C)alkoxy; and 15 Rp and Rq are independently selected from hydrogen, fluoro or methyl.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: 20 XA-YA-ZAwherein XAis absent or [CRXaRXb]n, wherein n is an integer from 1 to 6, wherein each occurrence of RXaand RXbis independently selected from hydrogen, NRX1RX2, C3- 6cycloalkyl or (1-2C)alkyl; or RXaand RXbcan be linked such that, together with the 25 carbon to which they are attached, form a 3- to 6-membered cycloalkyl ring; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(ORY1)-, -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; 30 ZAis selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, C3-8cycloalkyl, aryl (e.g. phenyl), heterocyclyl (including a 4 to 7 membered monocyclic362 P360887GB1 heterocyclic or a fused bicyclic heterocyclic ring system, a spirocyclic heterocyclic ring system, or a bridged heterocyclic ring system) or heteroaryl (including a monocyclic or bicyclic heteroaryl ring system); and wherein ZAis optionally substituted by one or more substituents selected from (1-6C)- 5 alkyl, halo, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3- 8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alkyl, aryl(1-2C)alkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)ORZ1, OC(O)RZ1, C(O)N(RZ1)RZ2, N(RZ1)C(O)RZ2and S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; 10 and any (1-6C)alkyl, (2-6C)alkenyl, (1-6C)haloalkyl, heterocyclyl, heteroaryl, phenyl, C3-8cycloalkyl, C3-8cycloalkyl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, heteroaryl(1-2C)alky; or phenyl(1-2C)alkyl, in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, ORZ3, NRZ3RZ4or methyl; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl; and 15 RXN is selected from selected from hydrogen, (1-4C)alkyl, monocyclic heterocyclyl or C3- 6cycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, (1-4C)haloalkyl, (1-4C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3, C(O)ORZ3, OC(O)RZ3, C(O)N(RZ3)RZ4, N(RZ3)C(O)RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl. 20 3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZA25 wherein XAis absent or [CRXaH]n, wherein n is an integer selected from 1, 2 or 3, wherein RXais selected from hydrogen, NRX1RX2or C3-4cycloalkyl; wherein RX1and RX2are independently selected from hydrogen or methyl; YAis absent or selected from -O-, -C(O)-, -C(O)O-, -N(RY1)- or -C(O)-N(RY1)-, wherein 30 RY1is selected from hydrogen or methyl; ZAis selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, C3-6cycloalkyl, 4 to 12- membered mono- or bicyclic heterocyclyl (e.g. a fused, bridged or spirocyclic heterocyclic ring system) or mono- or bicyclic heteroaryl; and363 P360887GB1 wherein ZAis optionally substituted by one or more substituents selected from (1-4C)- alkyl, halo, (1-4C)haloalkyl, 4- to 6-membered heterocyclyl, C3-6cycloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)N(RZ1)RZ2or S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or (1-2C)alkyl; 5 and any alkyl, haloalkyl, 4- to 6-membered heterocyclyl or C3-6cycloalkyl in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, ORZ3, NRZ3RZ4; wherein RZ3and RZ4are each independently selected from hydrogen or methyl; RXN is selected from hydrogen, (1-4C)alkyl, monocyclic heterocyclyl or C3-6cycloalkyl, each of10 which being optionally substituted by one or more substituents selected from halo, (1-2C)- haloalkyl, (1-2C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3or C(O)ORZ3; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl.

4. A compound according to any one of the preceding claims, or a pharmaceutically 15 acceptable salt thereof, wherein RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZAwherein XAis absent or [CH2]n, wherein n is an integer selected from 1 or 2; 20 YAis absent or selected from -O-, -C(O)-, -C(O)O-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or methyl; ZAis selected from hydrogen, (1-4C)alkyl, (2-4C)alkenyl, C3-6cycloalkyl, 4 to 10- membered mono- or bicyclic heterocyclyl (e.g. a fused, bridged or spirocyclic heterocyclic ring system) or mono- or bicyclic heteroaryl; and 25 wherein ZAis optionally substituted by one or more substituents selected from (1-4C)- alkyl, halo, (1-4C)haloalkyl, 4- to 6-membered heterocyclyl, C3-6cycloalkyl, oxo, cyano, NRZ1RZ2, ORZ1, C(O)RZ1, C(O)N(RZ1)RZ2or S(O)0-2RZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; and any alkyl, haloalkyl, 4- to 6-membered heterocyclyl or C3-6cycloalkyl in a 30 substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, hydroxy, methoxy or NH2; and364 P360887GB1 RXNis selected from hydrogen, (1-4C)alkyl, monocyclic heterocyclyl or C3-6cycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, (1-2C)- haloalkyl, (1-2C)alkoxy; oxo, cyano, NRZ3RZ4, ORZ3, C(O)RZ3or C(O)ORZ3; wherein RZ3and RZ4are each independently selected from hydrogen or (1-2C)alkyl. 5 5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RW and RX are independently selected from hydrogen, halo, methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZA10 wherein XAis absent or [CH2]n, wherein n is an integer selected from 1, 2 or 3; YAis absent or selected from -C(O)-, -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is independently selected from hydrogen or methyl; ZAis selected from hydrogen, (1-6C)alkyl, C3-6cycloalkyl, or 4- to 6- membered 15 monocyclic heterocyclyl; and wherein ZAis optionally substituted by one or more substituents selected from (1-4C)- alkyl, halo, (1-2C)haloalkyl, 4- to 6-membered monocyclic heterocyclyl, C3-6cycloalkyl, oxo, cyano, NRZ1RZ2or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; 20 wherein any alkyl, haloalkyl, 4- to 6-membered heterocyclyl or C3-6cycloalkyl in a substituent on the ZAgroup is optionally further substituted by one or more of halo, cyano, oxo, hydroxy, methoxy or NH2; and RXN is selected from hydrogen, (1-6C)alkyl, hydrogen, 4 to 6 membered heterocyclyl or C3- 6cycloalkyl, each of which being optionally substituted by one or more substituents selected 25 from cyano, NRZ3RZ4, ORZ3, C(O)RZ3, C(O)ORZ3, OC(O)RZ3, C(O)N(RZ3)RZ4, N(RZ3)C(O)RZ4; wherein RZ3and RZ3are each independently selected from hydrogen or (1-2C)alkyl.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RWand RXare independently selected from hydrogen, halo, 30 methyl, cyano or a group RA; wherein RAis a group of the formula: XA-YA-ZAwherein365 P360887GB1 XAis absent or [CH2]n, wherein n is an integer selected from 1, 2 or 3; YAis absent or selected from -N(RY1)- or -C(O)-N(RY1)-, wherein RY1is independently selected from hydrogen or methyl; ZAis selected from hydrogen, (1-4C)alkyl, C3-6cycloalkyl or 4- to 6- membered 5 monocyclic heterocyclyl; and wherein ZAis optionally substituted by one or more substituents selected from NRZ1RZ2, or ORZ1; wherein RZ1and RZ2are each independently selected from hydrogen or methyl; and RXN is selected from hydrogen, (1-4C)alkyl optionally substituted by one or more substituents 10 selected from halo, cyano, NRZ3RZ4or ORZ3, wherein RZ3is selected from hydrogen or methyl.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RW and RX are independently selected from hydrogen, halo, 15 methyl, cyano or a group RA; wherein RAis a group with a formula selected from: , ,, , ,375 P360887GB1 RXor5 8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: a) X is selected from CRXor N; and W is CRW; wherein RWis a group RAas defined in any one of the preceding claims; and RXis selected from hydrogen, 10 fluoro or methyl, e.g. hydrogen or fluoro; or b) W is selected from CRW and N; and X is CRX; wherein RX is a group RAas defined in any one of the preceding claims; and RW is selected from hydrogen, fluoro or methyl, e.g. hydrogen or fluoro. 15 9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y is CRY; and RY is selected from hydrogen, halo, NH2, cyano or methyl optionally substituted with NH2, hydroxy or cyano; optionally wherein RY is hydrogen.376 P360887GB1 10. A compound according to any one of the preceding claims, wherein Z is CRZ; and RZis selected from hydrogen, halo, NH2, cyano, or methyl optionally substituted with NH2, hydroxy or cyano; optionally wherein RZis hydrogen or fluoro. 5 11. A compound according to any one of the preceding claims, wherein: RTis hydrogen; and / or RVis hydrogen; and / or Rpand Rqare each hydrogen. 10 12. A compound according to any one of the preceding claims, wherein R1a is hydrogen and R1bis methyl.

13. A compound according to any one of the preceding claims, wherein R3a, R3b, R4a and 15 R4b are each independently selected from hydrogen or halo; optionally R3a, R3b, R4a and R4b are each hydrogen.

14. A compound according to any one of the preceding claims, wherein R5 is selected from hydrogen, halo or methoxy; optionally wherein R5 is hydrogen; and / or 20 R7 is selected from hydrogen, halo, hydroxy or methoxy; optionally wherein R7 is selected from hydrogen or hydroxy; further optionally wherein R7 is hydrogen.

15. A compound according to any one of the preceding claims, wherein R6 is selected25 from hydrogen, hydroxy, cyano, amino, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)alkoxy, (1- 2C)haloalkoxy, 5- or 6 membered heteroaryl or phenyl; wherein any wherein any (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, 5- or 6 membered heteroaryl or phenyl is optionally substituted with one or more of hydroxy, cyano, amino, oxo, methyl, halo, halomethyl or methoxy;377 P360887GB1 optionally wherein R6is selected from hydrogen, hydroxy, cyano, amino, methyl, fluoromethyl (e.g. CF3, CHF2or CH2F), halo (e.g. F, Cl or Br), methoxy or fluoromethoxy; further optionally wherein R6is selected from fluoro, chloro or trifluoromethyl. 5 16. A compound according to any one of the preceding claims, wherein R6 is selected from trifluoromethyl or chloro.

17. A compound according to any one of the preceding claims, wherein R8 is selected from hydrogen, hydroxy, cyano, amino, methyl, halo, trifluoromethyl, methoxy, 5- or 6 10 membered heteroaryl and phenyl; wherein any methyl, 5- or 6 membered heteroaryl and phenyl is optionally substituted with one or more of hydroxy, cyano, amino, oxo, methyl, halo, halomethyl or methoxy; optionally wherein R8 is selected from hydrogen, hydroxy, methyl, halo (e.g. F, Cl or Br), methoxy, 5- or 6- membered heteroaryl and phenyl; wherein any methyl, 5- or 6 membered 15 heteroaryl and phenyl is optionally substituted with one or more of halo, hydroxy, cyano or amino.

18. A compound according to any one of the preceding claims, wherein R8 is selected from hydrogen, hydroxy, methyl, fluoro, chloro, bromo, methoxy, fluoromethyl or 20 fluoromethoxy; optionally wherein R8 is selected from hydrogen, fluoro or chloro; further optionally wherein R8 is selected from hydrogen or chloro.

19. A compound according to any one of the preceding claims, wherein the compound is 25 of Formula (Ia), (Ib) or (IIa) below:378 P360887GB1 5(IIa) wherein: 10 RW, RX, RXN, R1a, R1b, R6, R8, and Rzare each as defined in any one of the preceding claims; X is C-RXa1or N; wherein RXa1is selected from hydrogen, halo, methyl or cyano; W is C-RWa1or N; wherein RWa1is selected from hydrogen, halo, methyl or cyano;379 P360887GB1 optionally wherein the compound is of Formula (Ic), (Id), (Ie), (If) or (IIb) below: 5 10(Ie)380 P360887GB1 5 whe RW, RX, RXN, R6, R8, and Rzare each as defined in any one of the preceding claims. 10 20. A compound selected from: 6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1-one; 6-[[2-oxo-2-(1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]amino]-2H-isoquinolin-1- one; 7-fluoro-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1- 15 one; 8-fluoro-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 20 6-[[2-(1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1-one;381 P360887GB1 6-[[2-(8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 6-[[2-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 5 6-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 6-[[2-(6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- 10 isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- 2H-isoquinolin-1-one; 15 7-fluoro-6-[[2-oxo-2-(1,1,6-trimethyl-3,4-dihydroisoquinolin-2-yl)ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-[(1S)-1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H-isoquinolin-1- one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- 20 isoquinolin-1-one; 7-[[2-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro- 3H-quinazolin-4-one; 25 6-fluoro-7-[[2-oxo-2-[(1S)-8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-quinazolin-4-one 6-[[2-oxo-2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]-2H- isoquinolin-1-one; 30 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 7-[[2-(8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6- fluoro-3H-quinazolin-4-one; 7-[[2-(6-chloro-8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6- 35 fluoro-3H-quinazolin-4-one; 6-fluoro-7-[[2-(8-fluoro-1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one;382 P360887GB1 6-fluoro-7-{[2-(6-fluoro-1,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]amino}- 3,4-dihydroquinazolin-4-one; 6-[[2-(5-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 5 7-fluoro-6-[[2-(7-hydroxy-6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-2H-isoquinolin-1-one; 7-fluoro-6-[[2-(7-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 7-fluoro-6-[[2-(7-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- 10 isoquinolin-1-one; 6-[[2-(8-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H- isoquinolin-1-one; 3-methyl-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 15 2-amino-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-quinazolin-4- one; 6-[[2-[1-(difluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 2-methyl-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-quinazolin- 20 4-one; 3-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7H-pyrido[2,3- d]pyridazin-8-one; 7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H-pyrido[3,2- d]pyrimidin-4-one; 25 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-4,7-difluoro- 2H-isoquinolin-1-one; 7-[[2-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- methyl-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 30 methyl-3H-quinazolin-4-one; (R)- 7‐({2‐[8‐chloro‐6‐fluoro‐1‐methyl‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl]‐2‐oxoethyl}amino)‐6‐fluor o‐3,4‐dihydroquinazolin‐4‐one; (S)-35 6‐({2‐[6,8‐dichloro‐1‐methyl‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl]‐2‐oxoethyl}amino)‐7‐fluoro‐1, 2‐dihydroisoquinolin‐1‐one;383 P360887GB1 7-fluoro-6-[[2-oxo-2-[(1S)-8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-1-one; 6-fluoro-2-methyl-7-[[2-oxo-2-[(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 5 2-amino-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6- fluoro-3H-quinazolin-4-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- phthalazin-1-one; 1-methyl-2-[2-[(1-oxo-2H-isoquinolin-6-yl)amino]acetyl]-3,4-dihydro-1H-isoquinoline-6- 10 carbonitrile; 6-[[2-(1-methyl-6-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-isoquinolin- 1-one; 6-fluoro-7-[[2-[1-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 15 6-fluoro-7-[[2-[1-methyl-6-(1H-pyrazol-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-2-methyl-7-[[2-[1-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-2-methyl-7-[[2-[1-methyl-6-(1H-pyrazol-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- 20 ethyl]amino]-3H-quinazolin-4-one; 6-fluoro-7-[[2-(6-isoxazol-4-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]- 2-methyl-3H-quinazolin-4-one; 7-[[2-[6-(3-aminophenyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6- fluoro-2-methyl-3H-quinazolin-4-one; 25 6-fluoro-2-methyl-7-[[2-[1-methyl-6-(3-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]- 3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]- 30 3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-(6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-oxo-2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one; 35 2-(3-aminopropylamino)-7-[[2-oxo-2-[(1R)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-3H-quinazolin-4-one;384 P360887GB1 2-(3-aminopropylamino)-7-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 5 2-(4-aminobutylamino)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-3H-quinazolin-4-one; 2-(3-aminopropylamino)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(4-aminobutylamino)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- 10 ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (4-hydroxybutylamino)-3H-quinazolin-4-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3-piperazin- 1-yl-2H-isoquinolin-1-one; 15 3-(2-aminoethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-2H-isoquinolin-1-one; 3-(aminomethyl)-6-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 3-[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1-oxo-2H- 20 isoquinolin-3-yl]propanamide; 3-[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinolin-3-yl]propanenitrile; 3-(aminomethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 25 3-(3-aminopropyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxybutyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3- 30 [(dimethylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 3-(azetidin-3-yl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(3-aminopropyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 35 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-piperidyl)-2H-isoquinolin-1-one;385 P360887GB1 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (pyrrolidin-3-ylmethyl)-2H-isoquinolin-1-one; 3-(4-aminobutyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 5 3-(3-aminopropyl)-7-fluoro-6-[[2-oxo-2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin-1-one; 3-(3-aminopropyl)-7-fluoro-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- 10 (piperazin-1-ylmethyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (morpholinomethyl)-2H-isoquinolin-1-one; 3-(1-amino-1-methyl-ethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 15 3-(1-aminocyclopentyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-(1-aminocyclopropyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- 20 (4-piperidylmethyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-piperidyl)-2H-isoquinolin-1-one; 3-(aminomethyl)-6-[[2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 25 7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1H-quinazoline-2,4- dione; 3-[6-[[2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-1-oxo-2H-isoquinolin-3-yl]propanamide; 3-(2-aminoethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- 30 ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 3-[7-fluoro-1-oxo-6-[[2-oxo-2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-3-yl]propanenitrile; 3-[7-fluoro-1-oxo-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-3-yl]propanenitrile; 35 3-[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinolin-3-yl]benzonitrile;386 P360887GB1 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-pyridyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (3-pyridyl)-2H-isoquinolin-1-one; 5 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- pyrimidin-5-yl-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- thiazol-5-yl-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3-[4- 10 (hydroxymethyl)phenyl]-2H-isoquinolin-1-one; 6-[[2-oxo-2-[(1S)-1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin- 1-one; 6-[[2-oxo-2-[(1R)-1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]-2H-isoquinolin- 1-one; 15 2-(4-aminobutyl)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 2-(5-aminopentyl)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 2-(3-aminopropyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- 20 ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(4-aminobutyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-(aminomethyl)-7-[[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 25 2-(aminomethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- pyrrolidin-3-yl-3H-quinazolin-4-one; 2-(3-aminopropyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- 30 ethyl]amino]-3H-quinazolin-4-one; 2-[(R)-amino(cyclopropyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- piperazin-2-yl-3H-quinazolin-4-one; 35 2-[(1-aminocyclopropyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one;387 P360887GB1 3-(aminomethyl)-7-fluoro-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin- 2-yl]ethyl]amino]-2H-isoquinolin-1-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2- [(dimethylamino)methyl]-6-fluoro-3H-quinazolin-4-one; 5 2-(azetidin-1-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2- (ethylaminomethyl)-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 10 (piperazin-1-ylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (pyrrolidin-1-ylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2-hydroxyethylamino)methyl]-3H-quinazolin-4-one; 15 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (morpholinomethyl)-3H-quinazolin-4-one; 2-[(4-acetylpiperazin-1-yl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2- 20 (morpholinomethyl)-3H-quinazolin-4-one; 2-[(3-aminopropylamino)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[(2- fluoroethylamino)methyl]-3H-quinazolin-4-one; 25 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[(2,2- difluoroethylamino)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[(2,2,2- trifluoroethylamino)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 30 (4-piperidyl)-3H-quinazolin-4-one; 2-[(S)-amino(cyclopropyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-methylpiperazin-1-yl)methyl]-3H-quinazolin-4-one; 35 2-[(4-amino-1-piperidyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one;388 P360887GB1 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-piperidylamino)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- (piperazin-1-ylmethyl)-3H-quinazolin-4-one; 5 7-((2-((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((S)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-((2-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((S)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-((2-((S)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 10 2-((R)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-((2-((R)-6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro- 2-((R)-pyrrolidin-3-yl)quinazolin-4(3H)-one 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- pyrrolidin-3-yl-3H-quinazolin-4-one; 15 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (1-methyl-4-piperidyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2R)-morpholin-2-yl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 20 [(2S)-morpholin-2-yl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(3R)-3-piperidyl]-3H-quinazolin-4-one; 2-(4-aminocyclohexyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 25 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(3S)-3-piperidyl]-3H-quinazolin-4-one; 2-(1-aminocyclopropyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 30 (2-piperidylmethyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (3-piperidylmethyl)-3H-quinazolin-4-one; 2-[(1R)-1-aminoethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 35 2-[(1S)-1-aminoethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one;389 P360887GB1 2-[(1R)-1-amino-2-methyl-propyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(1S)-1-amino-2-methyl-propyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 5 2-[(S)-amino(phenyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(R)-amino(phenyl)methyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 10 (4-hydroxycyclohexyl)-3H-quinazolin-4-one; 2-[(2R)-2-amino-2-cyclopropyl-ethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin- 2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 4-[7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-4- oxo-3H-quinazolin-2-yl]cyclohexanecarbonitrile; 15 2-(3-aminopropyl)-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(4-methylpiperazin-1-yl)methyl]-3H-quinazolin-4-one; 2-[(4-amino-1-piperidyl)methyl]-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- 20 yl]-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3R)-pyrrolidin-3-yl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3S)-pyrrolidin-3-yl]-3H-quinazolin-4-one; 25 2-[(R)-amino(cyclopropyl)methyl]-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl]-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 30 [(3-oxopiperazin-1-yl)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-isopropylpiperazin-1-yl)methyl]-3H-quinazolin-4-one; 2-(1,4-diazepan-1-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 35 2-(4,7-diazaspiro[2.5]octan-7-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one;390 P360887GB1 2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl- 3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-3H-quinazolin-4-one; 5 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3S)-3-hydroxypyrrolidin-1-yl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[4-hydroxy-4-(trifluoromethyl)-1-piperidyl]methyl]-3H-quinazolin-4-one; 1-[[7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro- 10 4-oxo-3H-quinazolin-2-yl]methyl]piperidine-4-carbonitrile; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[4-(oxetan-3-yl)piperazin-1-yl]methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2-[[3-(3,3- difluoroazetidin-1-yl)azetidin-1-yl]methyl]-6-fluoro-3H-quinazolin-4-one; 15 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-fluoropyrrolidin-1-yl]methyl]-3H-quinazolin-4-one; 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-ylmethyl)-7-[[2-(6,8-dichloro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- 20 (2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3H-quinazolin-4-one; 2-(4-aminobutyl)-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(2R)-2-piperidyl]-3H-quinazolin-4-one; 25 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (4-pyridyl)-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (3-pyridyl)-3H-quinazolin-4-one; 2-[1-(aminomethyl)cyclopropyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 30 2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 2-[(1S)-1,5-diaminopentyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2- oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (piperazin-2-ylmethyl)-3H-quinazolin-4-one; 35 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3H-quinazolin-4-one;391 P360887GB1 2-(aminomethyl)-7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3-hydroxyazetidin-3-yl)methyl]-3H-quinazolin-4-one; 5 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3-hydroxy-3-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [(4-hydroxy-4-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- 10 [(4-hydroxy-4-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-1H- quinazoline-2,4-dione; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- (hydroxymethyl)-3H-quinazolin-4-one; 15 methyl 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-1-oxo-2H-isoquinoline-3-carboxylate; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinoline-3-carboxylic acid; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- 20 (piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (morpholine-4-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-2H-isoquinoline-3-carboxamide; 25 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxypiperidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-hydroxy-4-methyl-piperidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- 30 (2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (4-methylpiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(3S)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 35 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- (oxetan-3-ylmethyl)-1-oxo-2H-isoquinoline-3-carboxamide;392 P360887GB1 6-[[2-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H-2,7-naphthyridin-1- one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- tetrahydrofuran-3-yl-3H-quinazolin-4-one; 5 2-[(1R)-1-amino-2-hydroxy-ethyl]-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- yl)-2-oxo-ethyl]amino]-6-fluoro-3H-quinazolin-4-one; 3-[7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-4- oxo-3H-quinazolin-2-yl]propanenitrile; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- 10 (2-hydroxyethyl)-1-oxo-2H-isoquinoline-3-carboxamide; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- pyrazin-2-yl-3H-quinazolin-4-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N,N- dimethyl-1-oxo-2H-isoquinoline-3-carboxamide; 15 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-N-(tetrahydrofuran-3-ylmethyl)-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-N-(tetrahydrofuran-3-ylmethyl)-2H-isoquinoline-3-carboxamide; 3-[(3S)-3-aminopyrrolidine-1-carbonyl]-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- 20 isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (2-oxa-5-azabicyclo[2.2.2]octane-5-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 25 N-(cyanomethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 3-(4,7-diazaspiro[2.5]octane-7-carbonyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3-[4- 30 (oxetan-3-yl)piperazine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-fluoropyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 3-(3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 35 N-(2-aminoethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide;393 P360887GB1 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxyethyl)-N-methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-N-[2- (dimethylamino)ethyl]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 5 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (hydroxymethyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- 10 (2-hydroxyethyl)-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (1-hydroxycyclopropyl)-2H-isoquinolin-1-one; 2-[[6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro- 1-oxo-2H-isoquinolin-3-yl]methylamino]acetonitrile; 15 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (methylaminomethyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- [(4-methylpiperazin-1-yl)methyl]-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- 20 [[(3R)-3-fluoropyrrolidin-1-yl]methyl]-2H-isoquinolin-1-one; methyl 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1- oxo-2H-isoquinoline-4-carboxylate; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-4- (piperazine-1-carbonyl)-2H-isoquinolin-1-one; 25 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1-oxo-2H- isoquinoline-4-carbonitrile; 6-[[2-[8-chloro-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- 3-(piperazin-4-ium-1-carbonyl)-2H-isoquinolin-1-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- 30 [((3S)-3-hydroxy-3-piperidyl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [((3R)-3-hydroxy-3-piperidyl)methyl]-3H-quinazolin-4-one; (S)-7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro- 3H-quinazolin-4-one; 35 7-fluoro-6-[[2-oxo-2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]- 3-(piperazine-1-carbonyl)-2H-isoquinolin-1-one;394 P360887GB1 7-fluoro-6-[[2-oxo-2-[(1R)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]amino]- 3-(piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-N-(2- hydroxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 5 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-4- (hydroxymethyl)isoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-N-(2- (dimethylamino)ethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-N-methyl-1- 10 oxo-1,2-dihydroisoquinoline-4-carboxamide; N-(cyanomethyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-1-oxo-1,2- dihydroisoquinoline-4-carboxamide; 15 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-N,N- dimethyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 7-fluoro-6-[[2-[(1S)-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 6-[[2-(6-chloro-8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- 20 fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-(6-fluoro-1,8-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 7-fluoro-6-[[2-(8-fluoro-1,6-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 25 7-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 6-fluoro-7-[[2-[(1S)-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3H- quinazolin-4-one; 6-[[2-[(1S)-6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- 30 2H-isoquinolin-1-one; 7-[[2-(8-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-3H- quinazolin-4-one; 7-fluoro-6-[[2-(6-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 35 6-[[2-[6-(difluoromethoxy)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one;395 P360887GB1 6-[[2-(5-bromo-6-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-(6-fluoro-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl)-2-oxo-ethyl]amino]-2H- isoquinolin-1-one; 5 6-[[2-(6,8-dimethoxy-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro- 2H-isoquinolin-1-one; 6-[[2-[(1S)-6-(difluoromethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-[1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- 10 ethyl]amino]-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-[(1S)-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-[(1R)-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2- yl]ethyl]amino]-2H-isoquinolin-1-one; 15 6-[[2-[(1R)-8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-8-chloro-1-methyl-6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-3-(3,3- 20 difluoro-1,6-diazaspiro[3.3]heptane-6-carbonyl)-7-fluoroisoquinolin-1(2H)-one; 3-(2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 3-(2,5-diazabicyclo[4.1.0]heptane-2-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 25 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3- (4,7-diazaspiro[2.5]octane-4-carbonyl)isoquinolin-1(2H)-one; 3-(3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 3-[(3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carbonyl]-6-[[2-(6,8-dichloro-1-methyl-3,4- 30 dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-N,N-dimethyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-N- (2-methoxyethyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; 35 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(4- methyl-4,7-diazaspiro[2.5]octane-7-carbonyl)isoquinolin-1(2H)-one;396 P360887GB1 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(7- methyl-4,7-diazaspiro[2.5]octane-4-carbonyl)isoquinolin-1(2H)-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(6- methyl-3,6-diazabicyclo[3.1.0]hexane-3-carbonyl)isoquinolin-1(2H)-one; 5 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-3-(3,3- difluoroazetidine-1-carbonyl)-7-fluoroisoquinolin-1(2H)-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (6-methyl-1,6-diazaspiro[3.3]heptane-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- 10 (1-methyl-1,6-diazaspiro[3.3]heptane-6-carbonyl)-2H-isoquinolin-1-one; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2H-isoquinolin-1-one; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3-(3- fluoroazetidine-1-carbonyl)isoquinolin-1(2H)-one; 15 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-N- (3-fluorocyclobutyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; 6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-7-fluoro-3- (3-fluoro-[1,3'-biazetidine]-1'-carbonyl) isoquinolin-1(2H)-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(3,3- 20 difluoropyrrolidine-1-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 3-[(3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carbonyl]-6-[[2-[(1S)-6-chloro-1-methyl-3,4- dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[3- (difluoromethyl)-3-hydroxy-pyrrolidine-1-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 25 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-methyl-3-oxo-piperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(3,3- 30 difluoroazetidine-1-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 3-[(3SR,4RS)-3-amino-4-(difluoromethyl)pyrrolidine-1-carbonyl]-6-[[2-[(1S)-6-chloro-1- methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 7-fluoro-6-[[2-oxo-2-(1,6,8-trimethyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]amino]-2H- isoquinolin-1-one; 35 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-fluoropyrrolidine-1-carbonyl]-2H-isoquinolin-1-one;397 P360887GB1 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxyethyl)-N-methyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-N-vinyl-2H-isoquinoline-3-carboxamide; 5 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (morpholine-4-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (4-isopropylpiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- 10 (4-methylpiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro- N,N-dimethyl-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-2H-isoquinoline-3-carboxamide; 15 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-N- (cyanomethyl)-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3S)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- 20 (3-oxopiperazine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- (3-fluorocyclobutyl)-1-oxo-2H-isoquinoline-3-carboxamide; 3-[(3S)-3-aminopyrrolidine-1-carbonyl]-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H- isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 25 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(4,7- diazaspiro[2.5]octane-7-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3R)-3-hydroxypyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 3-(4-acetylpiperazine-1-carbonyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2- 30 yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[(5R)-1,4- diazabicyclo[3.2.1]octane-4-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[4-(2,2- difluoroethyl)piperazine-1-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 35 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [3-(trifluoromethyl)piperazine-1-carbonyl]-2H-isoquinolin-1-one;398 P360887GB1 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(2,5- diazabicyclo[4.1.0]heptane-2-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[(1R,4R)- 2,5-diazabicyclo[2.2.2]octane-2-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 5 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-[(1R,4R)- 2,5-diazabicyclo[2.2.2]octane-2-carbonyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [4-(2-hydroxyethyl)piperazine-1-carbonyl]-2H-isoquinolin-1-one; 3-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole-5-carbonyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4- 10 dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- (2-hydroxy-2-methyl-propyl)-N-methyl-1-oxo-2H-isoquinoline-3-carboxamide; 15 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3-(4,7- diazaspiro[2.5]octane-4-carbonyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-N- [(1-hydroxycyclopropyl)methyl]-1-oxo-2H-isoquinoline-3-carboxamide; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- 20 (4-hydroxypiperidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (3-hydroxyazetidine-1-carbonyl)-2H-isoquinolin-1-one; 25 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(3S)-3-hydroxy-3-methyl-pyrrolidine-1-carbonyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-N-[2- (dimethylamino)-2-oxo-ethyl]-7-fluoro-1-oxo-2H-isoquinoline-3-carboxamide; (S)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2- 30 oxoethyl)amino)-3-(piperazine-1-carbonyl)isoquinolin-1(2H)-one; (S)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-3-(4,7-diazaspiro[2.5]octane-4-carbonyl)isoquinolin-1(2H)-one; (S)-7-fluoro-N,N-dimethyl-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)- 2-oxoethyl)amino)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; 35 3-((S)-3-aminopyrrolidine-1-carbonyl)-7-fluoro-6-((2-((S)-1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one;399 P360887GB1 3-(3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-7-fluoro-6-((2-((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 3-(2,5-diazabicyclo[4.1.0]heptane-2-carbonyl)-7-fluoro-6-((2-((S)-1-methyl-6-(trifluoromethyl)- 3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 5 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-2-carbonyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-4- [(dimethylamino)methyl]-2H-phthalazin-1-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-1- 10 methyl-quinazoline-2,4-dione; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-1-[2- (dimethylamino)ethyl]-6-fluoro-quinazoline-2,4-dione; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-1- (2-hydroxyethyl)quinazoline-2,4-dione; 15 N-(2-(1H-pyrazol-3-yl)ethyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide; 4-((S)-3-aminopyrrolidine-1-carbonyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; methyl 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- 20 fluoro-1-oxo-2H-isoquinoline-4-carboxylate; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-1- oxo-2H-isoquinoline-4-carboxamide; 6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-N- methyl-1-oxo-2H-isoquinoline-4-carboxamide; 25 N-(cyanomethyl)-6-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo- ethyl]amino]-7-fluoro-1-oxo-2H-isoquinoline-4-carboxamide; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-7-fluoro- 1-oxo-1,2-dihydroisoquinoline-4-carboxamide; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro- 30 4-(hydroxymethyl)isoquinolin-1(2H)-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- (pyrrolidin-3-ylmethyl)-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [[(3S)-3-piperidyl]methyl]-3H-quinazolin-4-one; 35 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3S)-3-piperidyl]methyl]-3H-quinazolin-4-one;400 P360887GB1 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(3-hydroxypyrrolidin-3-yl)methyl]-3H-quinazolin-4-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-piperidyl]methyl]-3H-quinazolin-4-one; 5 (S)-2-(1-(aminomethyl)cyclopropyl)-7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl)amino)-6-fluoroquinazolin-4(3H)-one; 7-[[2-(6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-6-fluoro-2- [[(3R)-3-piperidyl]methyl]-3H-quinazolin-4-one; (S)-2-(1-(aminomethyl)cyclopropyl)-6-fluoro-7-((2-(1-methyl-6-(trifluoromethyl)-3,4- 10 dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)quinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- ((3-fluoroazetidin-1-yl)methyl)quinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-((3,3- difluoroazetidin-1-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 15 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- ((6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)quinazolin-4(3H)-one; 7-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-6-fluoro-2- [(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)methyl]-3H-quinazolin-4-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-((3,3- 20 difluoro-1,6-diazaspiro[3.3]heptan-6-yl)methyl)-6-fluoroquinazolin-4(3H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- ((3-fluoro-[1,3'-biazetidin]-1'-yl)methyl)quinazolin-4(3H)-one; 6-[[2-(6,8-difluoro-1-methyl-3,4-dihydro-1`-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7-fluoro-3- (hydroxymethyl)-2H-isoquinolin-1-one; 25 7-fluoro-6-[[2-[(1S)-6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- (hydroxymethyl)-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (hydroxymethyl)-2H-isoquinolin-1-one; 6-[[2-(6-chloro-8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]amino]-7- 30 fluoro-3-(hydroxymethyl)-2H-isoquinolin-1-one; 3-(aminomethyl)-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo- ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- (methylaminomethyl)-2H-isoquinolin-1-one; 35 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(dimethylamino)methyl]-7-fluoro-2H-isoquinolin-1-one;401 P360887GB1 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(cyclopropylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(cyclopropylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; 5 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- (ethylaminomethyl)-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-3- [(isopropylamino)methyl]-2H-isoquinolin-1-one; 3-[(tert-butylamino)methyl]-6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2- 10 oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 6-[[2-[(1S)-6-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-3- [(cyclopropylmethylamino)methyl]-7-fluoro-2H-isoquinolin-1-one; (S)-3-((cyclobutylamino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)- yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 15 (S)-3-(aminomethyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl) amino)-7-fluoroisoquinolin-1(2H)-one; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro- 3-((isopropylamino)methyl)isoquinolin-1(2H)-one; 7-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-6-fluoro-2- 20 (piperazin-1-ylmethyl)quinazolin-4(3H)-one; (S)-6-((2-(6-chloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoro-3- (methoxymethyl)isoquinolin-1(2H)-one; (S)-3-((tert-butylamino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)- 2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; 25 (S)-3-(((cyclopropylmethyl)amino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; (S)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-3- ((ethylamino)methyl)-7-fluoroisoquinolin-1(2H)-one; (S)-3-((cyclopropylamino)methyl)-6-((2-(6,8-dichloro-1-methyl-3,4-dihydroisoquinolin-2(1H)- 30 yl)-2-oxoethyl)amino)-7-fluoroisoquinolin-1(2H)-one; (S)-3-((dimethylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-((ethylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 35 (S)-3-(((cyclopropylmethyl)amino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one;402 P360887GB1 (S)-3-(aminomethyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2- oxoethyl)amino)-3-((methylamino)methyl)isoquinolin-1(2H)-one; 5 (S)-3-((cyclopropylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-((cyclobutylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-3-((tert-butylamino)methyl)-7-fluoro-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- 10 dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; (S)-7-fluoro-3-((isopropylamino)methyl)-6-((2-(1-methyl-6-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)isoquinolin-1(2H)-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]methyl]-2H-isoquinolin-1-one; 15 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]methyl]-2H-isoquinolin-1-one; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[(oxetan-3-ylamino)methyl]-2H-isoquinolin-1-one; 1-[[[6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- 20 fluoro-1-oxo-2H-isoquinolin-3-yl]methylamino]methyl]cyclopropanecarbonitrile; 6-[[2-[(1S)-6,8-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7- fluoro-3-[[(1-fluorocyclobutyl)methylamino]methyl]-2H-isoquinolin-1-one; or 3-[[[(1S)-1-cyclopropyl-2,2,2-trifluoro-ethyl]amino]methyl]-6-[[2-[(1S)-6,8-dichloro-1-methyl- 3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]amino]-7-fluoro-2H-isoquinolin-1-one; 25 or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 30 22. A combination comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents.403 P360887GB1 23. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 21, or a combination according to claim 22, for use in therapy. 5 24. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 21, or a combination according to claim 22, for use in the treatment of: i) a proliferative condition; ii) cancer; 10 iii) a cancer selected from lung cancer (e.g. non-small cell lung cancer including lung adenocarcinoma and lung squamous cell carcinoma), renal cancer, solid organ cancer, pancreatic cancer (including pancreatic ductal adenocarcinoma), hematopoietic cancers including leukemia (e.g. acute myeloid leukemia (AML) or chronic myeloid leukaemia), breast cancer 15 (including invasive breast carcinoma), bladder cancer (e.g. bladder carcinoma including urothelial (transitional cell) bladder cancer), hepatocellular carcinoma (including adult and paediatric hepatocellular carcinoma and hepatoblastoma), hepatic cholangiocarcinoma, squamous cell carcinoma (e.g. head, neck and esophageal squamous cell carcinoma, including 20 squamous cell carcinoma of the oral tongue, nasopharyngeal carcinoma), nasopharyngeal carcinoma, sarcoma (including dedifferentiated liposarcoma, well differentiated liposarcoma, fibrosarcoma and osteosarcoma), glioblastoma, adrenocortical carcinoma, melanoma, diffuse glioma, mature B- cell neoplasm, gastric cancer (e.g. gastric adenocarcinoma), esophagogastric 25 adenocarcinoma, pheochromocytoma, hepatocellular carcinoma, endometrial carcinoma, bladder urothelial carcinoma, colorectal cancer including colon adenocarcinoma and rectal adenocarcinoma, ovarian cancer (including epithelial ovarian carcinoma and ovarian epithelial tumor ), prostate carcinoma (including prostate adenocarcinoma), renal clear cell carcinoma 30 (including clear cell renal cell carcinoma (ccRCC)), non-clear cell carcinoma, glioma (including low grade glioma and glioblastoma multiforme / astrocytoma), intrahepatic cholangiocarcinoma, neuroblastoma, cervical cancer (including cervical squamous cell carcinoma and cervical adenocarcinoma) or Mesothelioma;404 P360887GB1 iv) leukaemia; optionally AML leukaemia or chronic myeloid leukaemia; or v) non-cancerous tumour growth (such as ameloblastoma) 25. A compound according to any one of claims 1 to 20, or a pharmaceutically 5 acceptable salt thereof, a pharmaceutical composition according to claim 21, or a combination according to claim 22, for use in the inhibition of METTL1 activity.

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