(hetero)aryl-carbonyl-heterobicyclic compounds as inhibitors of pms2 for cancer and degenerative illnesses

Abstract

The present invention relates to compounds of Formula (I) that target PMS2 proteins that are components of the DNA Mismatch Repair (MMR) process: (I) wherein R2, R3, R4, R5, X, Y1, Y2, A1, A2, A3 and A4, and any groups associated therewith, are each as defined herein. 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 PMS2 activity is implicated.

Description

INHIBITOR COMPOUNDS INTRODUCTION

[0001] The present invention relates to certain compounds that function as inhibitors of PMS2 protein activity. In particular, the compounds of the present invention may be used as covalent binders to inhibit PMS2. Thus, the compounds of the present invention may be used to treat disease or conditions mediated, at least in part, by inappropriate PMS2 activity, for example, cancer. The invention furthermore relates to the use of the compounds and pharmaceutical compositions comprising them. BACKGROUND OF THE INVENTION

[0002] Cancer is caused by altered cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of molecular targets associated with key pathways that enable such malignancies.

[0003] Mismatch repair (MMR) is a highly conserved DNA repair pathway that plays a major role during DNA replication, repair, and recombination, as well as during meiosis in eukaryotes and immunoglobulin maturation / diversification in mammals. MMR promotes genome stability in all organisms by correcting DNA base mismatches and insertion / deletion (indel) loops that can occasionally arise during normal DNA replication process. Base pair mismatches occur when incorrect nucleotides are inserted into the newly synthesized DNA strand and escape the proofreading function of DNA polymerases. Indel loops commonly arise in the context of microsatellites - highly polymorphic short repetitive DNA sequences distributed throughout both prokaryotic and eukaryotic genomes. Typically, at microsatellites, the template and primer strands are prone to slippage (dissociation and reannealing) during replication, which can generate loop structures and a discordant number of repeat units between the template and newly synthesized strand.

[0004] DNA mismatch repair is a bidirectional excision and re-synthesis system that initiates at a defined strand scission 3′- or 5′- to a mismatch; the excision tract extends just past the mismatch. MMR can be divided into four steps: 1) mismatch recognition by MSH proteins; 2) recruitment of MLH / PMS proteins that connect the mismatch recognition signal to where the distant DNA strand scission begins; 3) excision of the errant DNA strand, and 4) re-synthesis of the excision gap using the remaining DNA strand as a template [1]. MMR is a highly conserved biological pathway. In humans, mismatch recognition by hMutSα (MSH2-MSH6) or hMutSβ (MSH2-MSH3) initiates the MMR pathway. Binding of hMutSα or hMutSβ to the mismatch siteresults in the recruitment of MutLα (MLH1-PMS2) to form a ternary complex whose protein- protein, protein-DNA interactions and endonuclease activity are modulated by ATP / ADP cofactors. Proliferating cell nuclear antigen (PCNA) may play a role in the recruitment of MMR proteins to the vicinity of the replication fork [1]. PCNA may also activate a latent endonuclease activity in eukaryotic MutLα proteins. After DNA incision, exonuclease 1 (EXO1) is recruited which excises the newly synthesized DNA strand and the DNA excision gap is re-synthesized by DNA polymerase ^ (Pol ^ ^). When DNA re-synthesis is complete, the remaining nick is ligated by DNA ligase to restore the integrity of the duplex [2]. Consistent with this function, MMR is an important tumor suppressor pathway that is lost in up to 40% of sporadic cancers. Moreover, individuals with germline mutations in MMR genes develop cancer predisposition conditions.

[0005] Lynch Syndrome (LS, formerly designated as hereditary non-polyposis colorectal cancer) is the most common cause of hereditary colorectal cancer (CRC), accounting for 2-5% of all cases. LS is also characterized by an increased risk of malignancies at certain extracolonic sites such as the endometrium, ovary, stomach and small bowel, among others [3]. LS has an autosomal dominant inheritance pattern and is caused by germline mutations in MMR genes MLH1, MSH2, MSH6 or PMS2. Gene expression from the one wild-type allele is sufficient for adequate MMR activity until a second hit inactivates the wild-type allele leading to MMR deficiency.

[0006] Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of four MMR genes, MLH1, MSH2, MSH6 or PMS2. Patients may have either homozygous biallelic alterations or heterozygous alterations of MMR genes.

[0007] MMR-deficient cancers are commonly and typically characterized by the accumulation of DNA mutations at higher rates than normal cells and other tumours; for example, CMMRD tumours commonly have an ultra-hypermutated phenotype (>250 substitution mutations / Mb) [4]. MMR deficiency also results in gains or losses in the repeat length of microsatellites, referred to as microsatellite instability (MSI). Cancers that possess more than 40% microsatellite variations (positive for two or more of five microsatellite markers routinely tested) are described as high frequency MSI (MSI-H). Tumours that have no MSI are microsatellite stable (MSS) and those that possess less than 40% microsatellite variations (one out of the five markers showing microsatellite instability) are low frequency MSI (MSI-L) [5]. MSI analysis is a widely used diagnostic biomarker of MMR-deficient tumours and MSI status is linked with a high prevalence of frameshift (FS) mutations that can occur because of insertion / deletion within coding microsatellites. In addition to altering downstream functions of the protein, the FS creates a new amino acid sequence that serves as a substrate for antigen processing and presentation [6],stimulating the activation of CD8+ T cells (class I) and the “helper” function of CD4+ T cells (class II).

[0008] Cancers with a greater number of neoantigens are more prone to immune surveillance and have an increased likelihood of responding to immunotherapy [7]; higher neoantigen load is associated with overall lymphocytic infiltration, TILs, memory T cells, and survival in colorectal cancer [8, 9]. This feature supports a rationale for immunotherapy-based treatment strategies [6]. Consistent with this notion, immune checkpoint inhibitors now offer a significant therapeutic advance in the treatment of MMR-deficient (MMR-d) cancers. Inhibitors of PD-1; for example, pembrolizumab (Keytruda) and nivolumab (Opdivo), have been approved by the Food and Drug Administration (FDA) for patients with MMR-d or MSI-H metastatic CRC based upon the significant survival benefit they provide. The CTLA-4 inhibitor ipilimumab (Yervoy), has been approved for use in combination with nivolumab for the treatment of MMR-d or MSI-H CRC patients who were previously treated with chemotherapy. Importantly, the FDA has approved the use of pembrolizumab in MMR-d / MSI-H cancers regardless of histological tumour type

[0010] .

[0009] It is now accepted that clinical responses to immune checkpoint inhibitors require the existence of tumour neoantigens and infiltration of T cells that recognize such neoantigens. Higher neoantigen load is associated with response to CTLA-4 and PD-1 blockade in patients with melanoma and non-small-cell lung cancer [11, 12, 13]. The number of neoantigens is linked to tumour mutational burden (TMB), and several large studies have confirmed that high TMB correlates with enhanced checkpoint inhibitor responses and improved overall survival in certain tumour types, such as urothelial carcinoma

[0014] , non-small cell lung cancer [15-18] and small cell lung cancer

[0019] .

[0010] Germano et al. recently proposed that MMR inactivation through silencing of MLH1 increases TMB and leads to “dynamic mutational profiles”, resulting in persistent renewal of neoantigens both in vitro and in vivo. This triggers immune surveillance and leads to the control of tumour growth, particularly in combination with immune checkpoint inhibition, in mouse models

[0020] . Similar results are observed upon silencing of MSH2

[0021] .

[0011] Guan et al. and Lu et al. report that MLH1 deficiency leads to cytosolic DNA release, activation of the cGAS-STING pathway and IFN- ^ production. Guan et al. demonstrate that MLH1 loss leads to DNA hyperexcision, RPA exhaustion, chromosomal instability and accumulation of cytosolic DNA

[0022] . Lu et al. report that the sensing of cytosolic DNA by the cGAS STING pathway contributes to the clinical benefit of immunotherapy in patients harboring MMR-d tumours

[0023] . Together these reports suggest that abrogation of MMR activity may elicit beneficial immune activation through activation of the cGAS-STING pathway.

[0012] MLH1 and PMS2 commonly form a heterodimer; loss of MLH1 protein typically leads to concomitant loss of PMS2 protein suggesting that either or both proteins may be essential for MMR function and cGAS / STING pathway modulation.

[0013] There is therefore a biological and clinical rationale highlighting the need for inhibitors that target the PMS2 protein, a key component of DNA MMR, to reawaken an anti-tumour immune response.

[0014] Thus, the present invention provides methods for the treatment of cancer by binding to and modulating the function of the DNA MMR component PMS2 using small molecules as single agents and in combination with immunotherapy agents, other DNA damage response pathway modulators and / or standard-of-care chemotherapeutic agents.

[0015] Outside of the cancer field, triplet repeat disorders comprise over 30 human neurodegenerative and neuromuscular inherited diseases such as Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs). Such disorders are characterized by the expansion of simple repeats in genomic DNA. These unstable repeats are commonly found at different regions of several genes and their expansion can cause disease by a variety of both loss- and gain-of-function pathways, for instance through interfering with the expression or properties of the gene products, or by affecting splicing or antisense regulation. Several mechanisms including errors during DNA replication, meiotic recombination, transcription, DNA repair, and chromatin remodeling have been proposed to contribute to repeat instability, which can occur at various stages of the cell cycle. There is evidence that a functional MMR pathway is required for maintaining the stability of microsatellite sequences: for example, Msh2- / - transgenic mice bearing a copy of the human HD exon 1 (containing the CAG repeats) showed reduced expansion of the introduced (CAG)n repeats when compared with Msh2+ / + HD exon 1 mice counterparts

[0024] .

[0016] Thus, there is a further need for compounds that target components of the DNA MMR process, including PMS2, for treating triplet repeat disorders. The present invention was devised with the foregoing in mind. References 1. Martin-Lopez, J.V. and R. Fishel, The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome. Fam Cancer, 2013.12(2): p.159- 68. 2. Liu, D., G. Keijzers, and L.J. Rasmussen, DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res, 2017.773: p.174-187. 3. Lynch, H.T., et al., Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet, 2009.76(1): p.1-18.Shlien, A., et al., Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet, 2015.47(3): p.257- 62 Sehgal, R., et al., Lynch syndrome: an updated review. Genes (Basel), 2014.5(3): p.497- 507 Willis, J.A., et al., Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate. Clin Cancer Res, 2019. Gubin, M.M. and R.D. Schreiber, CANCER. The odds of immunotherapy success. Science, 2015.350(6257): p.158-9. Kloor, M. and M. von Knebel Doeberitz, The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer, 2016.2(3): p.121-133. Giannakis, M., et al., Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep, 2016.17(4): p.1206. Lemery, S., P. Keegan, and R. Pazdur, First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med, 2017.377(15): p.1409-1412. Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015.372(26): p.2509-20. Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD- 1 blockade in non-small cell lung cancer. Science, 2015.348(6230): p.124-8. Van Allen, E.M., et al., Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science, 2015.350(6257): p.207-211. Rosenberg, J.E., et al., Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet, 2016.387(10031): p.1909- 20. Hellmann, M.D., et al., Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell, 2018.33(5): p.843-852 e4. Rizvi, H., et al., Molecular Determinants of Response to Anti-Programmed Cell Death (PD)- 1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J Clin Oncol, 2018. 36(7): p.633-641. Carbone, D.P., et al., First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med, 2017.376(25): p.2415-2426. Hellmann, M.D., et al., Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med, 2018.378(22): p.2093-2104. Hellmann, M.D., et al., Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell, 2018.33(5): p.853-861 e4. Germano, G., et al., Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature, 2017.552(7683): p.116-120. Mandal, R., et al., Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science, 2019.364(6439): p.485-491. Guan J., et al., MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1 activates the cGAS-STING pathway. Cancer Cell.2021, 39 (1), 109 - 121, Lu, C., et al. DNA sensing in mismatch repair-deficient tumor cells is essential for anti- tumor immunity. Cancer Cell.2021, 39 (1), 96 - 108. Manley, K., et al., Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet, 1999.23(4): p.471-3.SUMMARY OF THE INVENTION

[0017] According to a first aspect of the present invention there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0018] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0019] According to a further aspect of the present invention, there is provided a method of inhibiting PMS2 activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0020] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which PMS2 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0021] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0022] According to a further aspect of the present invention, there is provided a method of treating cancer 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0023] According to a further aspect of the present invention, there is provided a method of treating a triplet repeat disorder (e.g. Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs)) 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0024] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical compositionas defined herein for use in therapy.

[0025] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use as a medicament.

[0026] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

[0027] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer.

[0028] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a triplet repeat disorder. In a particular embodiment, the triplet repeat disorder is selected from the group consisting of Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs).

[0029] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the inhibition of PMS2 activity.

[0030] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which PMS2 activity is implicated.

[0031] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative disorder.

[0032] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer.

[0033] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein,or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a triplet repeat disorder. In a particular embodiment, the triplet repeat disorder is selected from the group consisting of Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs).

[0034] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of PMS2 activity.

[0035] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which PMS2 activity is implicated.

[0036] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0037] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0038] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

[0039] In the above-outlined aspects of the invention, the proliferative disorder is suitably cancer, and the cancer is suitably a human cancer. In particular, the compounds of the present invention will be useful for the treatment of any cancer in which mis-match repair inhibition and / or cGAS / STING pathway activation is beneficial. Any suitable cancer may be targeted (e.g., adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann Syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé Syndrome, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, Carney Complex, central nervous system tumors, cervical cancer, colorectal cancer, Cowden Syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor – GIST, germ cell tumor, gestational trophoblastic disease, head and neck cancer,hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukamia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni Syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), Lymphoma (Hodgkin, non-Hodgkin), Lynch Syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia Type 1 & 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus Cancer, nasopharyngeal Cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung or pancreas), neurofibromatosis Type 1 & 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers Syndrome, pheochromocytoma, paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi or soft tissue), skin cancer, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom’s macroglobulinemia, Werner syndrome, Wilms Tumor and xeroderma pigmentosum). Particular cancers of interest include haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-oesophageal cancer, neuroendocrine cancers, osteosarcomas, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, oesophageal cancer, and ovarian cancer.

[0040] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0041] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0042] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, 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.

[0043] 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. It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

[0044] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, refer to animals (e.g., mammals), particularly humans. Suitably, the “subject(s)” and “patient(s)” may be a non-human animal (e.g., livestock and domestic pets) or a human.

[0045] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and / or physically compatible with other ingredients (such as, for example, with reference to a formulation), and / or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

[0046] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “(1-6C)alkyl” includes (1-4C)alkyl, (1- 3C)alkyl, propyl, isopropyl and t-butyl.

[0047] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0048] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), the ethylene isomers (–CH(CH3)– and – CH2CH2–), the propylene isomers (–CH(CH3)CH2–, –CH(CH2CH3)–, –C(CH3)2–, and – CH2CH2CH2–), pentylene (-CH2CH2CH2CH2CH2-), and the like.

[0049] The term “alkyenyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl and but-2,3-enyl and includes all possible geometric (E / Z) isomers.

[0050] The term “alkynyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0051] “(m-nC)cycloalkyl” means a saturated hydrocarbon ring system containing from m to n number of carbon atoms. Exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.

[0052] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and t-butoxy.

[0053] The term “cycloalkoxy” refers to O-linked cycloalkyl groups.

[0054] The term “haloalkyl” is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g., fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2 and -CF3.

[0055] The term “haloalkoxy” is used herein to refer to an alkoxy group in which one or more hydrogen atoms have been replaced by halogen (e.g., fluorine) atoms. Examples of haloalkoxy groups include -O-CH2F, -O-CHF2 and -O-CF3.

[0056] The term “halo”, “halogen” or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.

[0057] The term “carbocyclyl”, “carbocyclic” or “carbocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s). Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.

[0058] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H- thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups 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. Heterocycles may comprise 1 or 2 oxo (=O) or thioxo (=S) substituents. 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.

[0059] The phrase “bridged ring systems” means ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza- bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

[0060] The phrase “spiro bi-cyclic ring systems” means that the two ring systems share one common spiro carbon atom, i.e., the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0061] As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e., “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). An aromatic ring system can be substituted or unsubstituted.

[0062] As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.

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

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

[0065] 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.

[0066] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0067] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0068] 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.

[0069] 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.

[0070] 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 a particular embodiment, an aryl is phenyl.

[0071] The terms “[(m-nC)alkyl]amino” and “di-[(m-nC)alkyl]amino” refer to amino groups substituted with one or two (m-nC)alkyl groups, respectively.

[0072] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3- 6C)cycloalkyl. Likewise, hydroxy-(m-nC)alkyl, (m-nC)alkoxy-(m-nC)alkyl, cycloalkyl-(m-nC)alkyl, aryl-(m-nC)alkyl, heterocyclyl-(m-nC)alkyl and heteroaryl-(m-nC)alkyl will be understood by a person skilled in the art to mean (m-nC)alkyl substituted by hydroxy, (m-nC)alkoxy, cycloalkyl, aryl, heterocyclyl and heteroaryl, respectively. Similarly amino-(m-nC)alkyl, [(m-nC)alkyl]amino- (m-nC)alkyl, di-[(m-nC)alkyl]amino-(m-nC)alkyl and [(m-nC)alkyl][(m-nC)cycloalkyl]amino-(m- nC)alkyl will be understood by a person skilled in the art to mean (m-nC)alkyl substituted by amino, [(m-nC)alkyl]amino, di-[(m-nC)alkyl]amino and [(m-nC)alkyl][(m-nC)cycloalkyl]amino, respectively.

[0073] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. For example, the term “wherein any alkyl moiety present in R8Ais optionally substituted” or the term “wherein any alkoxy, cycloalkyl, aryl,heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted” suitably means that (any) one of the hydrogen radicals of the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais substituted by the relevant stipulated group.

[0074] 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. In some embodiments, one or more refers to one, two or three. In another embodiment, one or more refers to one or two. In a particular embodiment, one or more refers to one.

[0075] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

[0076] "About" when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value. Compounds

[0077] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below:wherein R2is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; R3is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy, amino-(1- 6C)alkyl or (1-6C)haloalkyl;R4is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (1- 6C)haloalkoxy or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen or (1-6C)alkyl; R5is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; or R4and R5are linked such that, together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl or a heteroaryl, wherein any 4-6 membered heterocyclyl or heteroaryl is optionally substituted by one or more RA, wherein each RAis independently selected from halo, cyano, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; X is N, CH or CR6, wherein R6is halo, cyano, (1-6C)alkyl or (1-6C)haloalkyl; Y1is -CH2-, C(=O)- or -CHRB, wherein RBis selected from halo, cyano, methyl, methoxy, CF3, - OCF3or hydroxymethyl; Y2is -CH2-, -C(=O)-, -CHRC-, -CH2-CH2-, -CH2-CHRC- or -CHRC-CH2-, wherein RCis selected from halo, cyano, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1is selected from N, CH, CR7or CR12; A2is selected from N, CH, CR7or CR12; A3is selected from N, CH or CR13; A4is selected from N, CH or CR14; with the proviso that: only one or two of A1, A2, A3or A4can be N; and one of A1and A2is CR7; R7is a group of the formula (IA) or (IB) shown below:(IA) (IB)wherein denotes the point of attachment to A1or A2, R8Ais hydrogen, (1-6C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, heterocyclyl-(1- 4C)alkyl, heteroaryl-(1-4C)alkyl or 8- to 12-membered carbocyclyl, wherein any alkyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3- 6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3- 6C)cycloalkyl or (3-6C)cycloalkoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3- 6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3- 6C)cycloalkyl or (3-6C)cycloalkoxy; R8is a group of the formula (IA-I) or (IA-II) shown below:(IA-I) (IA-II) wherein denotes the point of attachment, R8Band R8Dare each independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl and -C(O)NR8FR8G, wherein R8Fand R8Gare each independently selected from hydrogen or (1-4C)alkyl;wherein any alkyl moiety present in R8Band / or R8Dis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1- 6C)alkoxy, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any cycloalkyl moiety present in R8Band / or R8Dis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1- 6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; R8Cis selected from hydrogen, halo, (1-6C)alkyl, (1-6C)alkoxy, [(1-4C)alkyl]amino, di-[(1- 4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino- (1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, di[(3-6C)cycloalkyl]amino- (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl-(1-4C)alkyl, aryl-(1- 4C)alkyl, heterocyclyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl; wherein any alkyl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, NR8CAR8CB(wherein R8CAand R8CBare each independently selected from hydrogen and (1-6C)alkyl), (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1- 4C)alkoxy, (3-6C)cycloalkyl or (3-6C)cycloalkoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, NR8CCR8CD(wherein R8CCand R8CDare each independently selected from hydrogen and (1-6C)alkyl), (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl or (3-6C)cycloalkoxy; or R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl, wherein any 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl;R8Eis selected from the group consisting of hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, wherein any alkyl moiety present in R8Eis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3- 6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any cycloalkyl moiety present in R8Eis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1- 6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; R12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, (3-6C)cycloalkyl, wherein any (1- 2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1- 2C)alkoxy, or R12is -(CHRp)f-Z12, wherein Rp is hydrogen or methyl; f is 0 or 1; and Z12is -OR20, -NR21R22, -C(O)NR21R22or -NR23C(O)R24; wherein R20is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRq)e-(3-7C)cycloalkyl, -(CHRq)e-phenyl, -(CHRq)e-[4 to 6-membered heterocyclyl] or -(CHRq)e-[5 or 6 membered heteroaryl], wherein Rq is hydrogen or methyl; and e is 0 or 1; R21and R22are each independently selected from hydrogen, (1-6C)alkyl, (2- 6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRr)d-(3-7C)cycloalkyl, -(CHRr)d- phenyl, -(CHRr)d-[4 to 6-membered heterocyclyl] or -(CHRr)d-[5 or 6 membered heteroaryl], wherein Rr is hydrogen or methyl; and d is 0 or 1;or R21and R22are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; R23is hydrogen or (1-2C)alkyl; R24is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRs)c-(3-7C)cycloalkyl, -(CHRs)c-phenyl, -(CHRs)c-[4 to 6-membered heterocyclyl] or -(CHRs)c-[5 or 6 membered heteroaryl], wherein Rsis hydrogen or methyl; and c is 0 or 1; wherein each of R20, R21, R22, R23or R24or any ring formed when R21and R22are linked, is optionally substituted with one or more RD; R13is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1- 2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1- 2C)alkoxy, or R13is -(CHRo)h-Z13, wherein Ro is hydrogen or methyl; h is 0 or 1; and Z13is -OR25, -NR26R27, -C(O)NR26R27or -NR28C(O)R29; wherein R25is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRn)i-(3-7C)cycloalkyl, -(CHRn)i-phenyl, -(CHRn)i-[4 to 6-membered heterocyclyl] or -(CHRn)i-[5 or 6 membered heteroaryl], wherein Rn is hydrogen or methyl; and i is 0 or 1; R26and R27are each independently selected from hydrogen, (1-6C)alkyl, (2- 6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRm)j-(3-7C)cycloalkyl, -(CHRm)j-phenyl, -(CHRm)j-[4 to 6-membered heterocyclyl] or -(CHRm)j-[5 or 6 membered heteroaryl], wherein Rmis hydrogen or methyl; and j is 0 or 1; or R26and R27are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; R28is hydrogen or (1-2C)alkyl; R29is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRl)k-(3-7C)cycloalkyl, -(CHRl)k-phenyl, -(CHRl)k-[4 to 6-membered heterocyclyl] or -(CHRl)k-[5 or 6 membered heteroaryl], wherein Rlis hydrogen or methyl; and k is 0 or 1; wherein each of R25, R26, R27, R28or R29or any ring formed when R26and R27are linked, is optionally substituted with one or more RD; R14is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1- 2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1- 2C)alkoxy, or R14is -(CHRk)m-Z14, wherein Rk is hydrogen or methyl; m is 0 or 1; and Z14is -OR30, -NR31R32, -C(O)NR31R32or -NR33C(O)R34; wherein R30is (1-4C)alkyl, (3-7C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRj)o-(3-7C)cycloalkyl, -(CHRj)o- [4 to 6-membered heterocyclyl] or -(CHRj)o-[5 or 6 membered heteroaryl], wherein Rj is hydrogen or methyl; ando is 0 or 1; R31and R32are each independently selected from hydrogen, (1-6C)alkyl, (2- 6C)alkanoyl, (3-7C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRi)p-(3-7C)cycloalkyl, -(CHRi)p-[4 to 6-membered heterocyclyl] or -(CHRi)p-[5 or 6 membered heteroaryl], wherein Riis hydrogen or methyl; and p is 0 or 1; or R31and R32are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; R33is hydrogen or (1-2C)alkyl; R34is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRh)q-(3-7C)cycloalkyl, -(CHRh)q-[4 to 6-membered heterocyclyl] or -(CHRh)q-[5 or 6 membered heteroaryl], wherein Rhis hydrogen or methyl; and q is 0 or 1; wherein each of R30, R31, R32, R33or R34, or any ring formed when R31and R32are linked, is optionally substituted with one or more RD; and wherein each RDis independently selected from the group consisting of oxo, halo, cyano, hydroxy, (1-4C)alkyl, or a group: -L1-X1-Q1wherein: L1is absent or (1-2C)alkylene; X1is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, - S(O)0-2-, -C(O)-N(R15)-, -N(R15)-C(O)-, -NR15-, -N(R15)-C(O)-NR15-, -SO2N(R15)-, or - N(R15)SO2-, where each R15is independently selected from hydrogen or (1-4C)alkyl; andQ1is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2- 4C)alkynyl, or (3-6C)cycloalkyl.

[0078] In another aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below:wherein R2, R5, X, Y1, Y2, A1, A2, A3and A4are as defined above; R3is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; and R4is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen or (1-6C)alkyl.

[0079] Particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of R2, R3, R4, R5, X, Y1, Y2, A1, A2, A3, A4, and any groups associated therewith, have any of the meanings defined herein or in any of paragraphs (1) to (111): (1) R2is hydrogen, halo, hydroxy, (1-4C)alkyl, (1-4C)alkoxy or (1-4C)haloalkyl; (2) R2is hydrogen, halo, hydroxy, (1-3C)alkyl, (1-3C)alkoxy or (1-3C)haloalkyl; (3) R2is hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, methoxy, ethoxy, CH2F, CHF2or CF3; (4) R2is hydrogen, fluoro, chloro, hydroxy, methyl, methoxy or CHF2; (5) R2is hydrogen or hydroxy; (6) R3is hydrogen, halo, hydroxy, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy, amino-(1- 4C)alkyl or (1-4C)haloalkyl; (7) R3is hydrogen, halo, hydroxy, (1-3C)alkyl, hydroxy-(1-3C)alkyl, (1-3C)alkoxy, amino-(1- 3C)alkyl or (1-3C)haloalkyl;(8) R3is hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, aminomethyl, aminoethyl, CH2F, CHF2or CF3; (9) R3is hydrogen, fluoro, chloro, hydroxy, methyl, hydroxymethyl, methoxy or aminomethyl; (10) R3is hydrogen or methyl; (11) R4is hydrogen, halo, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1- 4C)haloalkoxy or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen or (1-4C)alkyl; (12) R4is hydrogen, halo, hydroxy, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1- 3C)haloalkoxy or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen or (1-3C)alkyl; (13) R4is hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, CH2F, CHF2, CF3, O- CH2F, O-CHF2, O-CF3or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen, methyl or ethyl; (14) R4is hydrogen, fluoro, hydroxy, methoxy, CHF2, O-CHF2 or NH2; (15) R4is hydrogen, hydroxy or methoxy; (16) R5is hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy or (1-4C)haloalkyl; (17) R5is hydrogen, halo, cyano, hydroxy, (1-3C)alkyl, (1-3C)alkoxy or (1-3C)haloalkyl; (18) R5is hydrogen, fluoro, chloro, bromo, cyano, hydroxy, methyl, ethyl, propyl (e.g., n-propyl or i-propyl), butyl (e.g., n-butyl, i-butyl or t-butyl), methoxy, ethoxy, CH2F, CHF2 or CF3. (19) R5is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl (e.g., n-propyl or i- propyl), butyl (e.g., n-butyl, i-butyl or t-butyl), methoxy or CF3. (20) R5is hydrogen, chloro, methyl, propyl (e.g., i-propyl),butyl (e.g., t-butyl) or CF3; (21) R4and R5are linked such that, together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein any 5-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one, two or three RA; (22) R4and R5are linked such that, together with the atoms to which they are attached, they form a 5-6 membered nitrogen- or oxygen-containing heterocyclyl or a 5-6 membered nitrogen- or oxygen-containing heteroaryl, wherein any 5-6 membered nitrogen- or oxygen- containing heterocyclyl or 5-6 membered nitrogen- or oxygen-containing heteroaryl is optionally substituted by one, two or three RA; (23) R4and R5are linked such that, together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocyclyl or a 5-membered nitrogen-containing heteroaryl, wherein any 5-membered nitrogen-containing heterocyclyl or 5-membered nitrogen-containing heteroaryl is optionally substituted by one, two or three RA; (24) R4and R5are linked such that, together with the atoms to which they are attached, they form a 5-membered heterocyclyl comprising 1 or 2 nitrogen atoms or a 5-memberedheteroaryl comprising 1 or 2 nitrogen atoms, wherein any 5-membered heterocyclyl or 5- membered heteroaryl is optionally substituted by one, two or three RA; (25) R4and R5are linked such that, together with the atoms to which they are attached, they form a pyrrolidine ring, an isoxazole ring, a dihydroisoxazole ring, a pyrrole ring, a dihydropyrrole ring, a pyrazole ring or a dihydropyrazole ring, any of which is optionally substituted by one, two or three RA; (26) R4and R5are linked such that, together with the atoms to which they are attached, they form a pyrrolidine ring, a dihydroisoxazole ring, a dihydropyrrole ring or a dihydropyrazole ring, any of which is optionally substituted by one, two or three RA. (27) R4and R5are linked such that, together with the atoms to which they are attached, they form a ring selected from the following:or, wherein denotes the bond separating the carbon atoms to which R4and R5are attached, and RAis as defined anywhere herein; (28) Each RAis independently selected from halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1- 4C)alkoxy or (1-4C)haloalkyl; (29) Each RAis independently selected from fluoro, chloro, bromo, hydroxy, oxo, (1-3C)alkyl, (1-3C)alkoxy or (1-3C)haloalkyl; (30) Each RAis independently selected from fluoro, chloro, bromo, hydroxy, oxo, methyl, ethyl, methoxy or ethoxy; (31) Each RAis independently selected from fluoro, chloro, hydroxy, oxo, methyl or ethyl; (32) Each RAis independently oxo or methyl; (33) X is N, CH or CR6, wherein R6is halo, cyano, (1-4C)alkyl or (1-4C)haloalkyl; (34) X is N, CH or CR6, wherein R6is fluoro, chloro, bromo, cyano, (1-3C)alkyl or (1- 3C)haloalkyl; (35) X is N, CH, C-Cl, C-F, C-Br, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2 or C-CF3; (36) X is N, CH, C-Cl, C-F, C-CN, C-CH3, C-CHF2 or C-CF3; (37) Y1is -CH2-, C(=O)- or -CHRB, wherein RBis selected from fluoro, chloro, bromo, methyl, methoxy or hydroxymethyl; (38) Y1is -CH2- or C(=O)-; (39) Y1is -CH2-;(40) Y2is -CH2-, -C(=O)-, -CHRC-, -CH2-CH2-, -CH2-CHRC- or -CHRC-CH2-, wherein RCis selected from fluoro, chloro, bromo, methyl, methoxy or hydroxymethyl; (41) Y2is -CH2-, -C(=O)-, or -CH2-CH2-; (42) Y2is -CH2- or -CH2-CH2-; (43) Y1is -CH2- and / or Y2is -CH2- or -CH2-CH2-; (44) A1is selected from N, CH, CR7or CR12; A2is selected from N, CH, CR7or CR12; A3is selected from N, CH or CR13; A4is selected from N, CH or CR14; with the proviso that: only one of A1, A2, A3or A4can be N; one of A1and A2is CR7; A3cannot be CR13when A4is CR14; and A4cannot be CR14when A3is CR13; (45) A1is selected from CH, CR7or CR12; A2is selected from CH, CR7or CR12; A3is selected from N, CH or CR13; A4is selected from N, CH or CR14; with the proviso that: only one of A1, A2, A3or A4can be N; one of A1and A2is CR7; A3cannot be CR13when A4is CR14; and A4cannot be CR14when A3is CR13; (46) A1is selected from CH or CR7; A2is selected from CH, CR7or CR12; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that: one of A1and A2is CR7; A3cannot be CR13when A4is CR14; and A4cannot be CR14when A3is CR13; (47) A1is CR7; A2is selected from CH or CR12; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that: A3cannot be CR13when A4is CR14; andA4cannot be CR14when A3is CR13; (48) A1is CR7; A2is selected from CH or CR12; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that: A3cannot be CR13when A4is CR14; A4cannot be CR14when A3is CR13; and A2can only be CR12when A3and A4are CH; (49) A1is CR7; A2is selected from CH or CR12; A3is CH; A4is CH; (50) A1is CR7; A2is CH; A3is CH or CR13; A4is CH; (51) A1is CR7; A2is CH; A3is CH; A4is selected from CH or CR14; (52) A1is CR7; A2is CH; A3is CH; A4is CH; (53) A1is CH or CR12; A2is CR7; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that: A3cannot be CR13when A4is CR14; and A4cannot be CR14when A3is CR13; (54) A1is CH or CR12; A2is CR7; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that:A3cannot be CR13when A4is CR14; A4cannot be CR14when A3is CR13; and A1can only be CR12when A3and A4are CH; (55) A1is CH or CR12; A2is CR7; A3is CH; A4is CH; (56) A1is CH; A2is CR7; A3is selected from CH or CR13; A4is CH; (57) A1is CH; A2is CR7; A3is CH; A4is selected from CH or CR14; (58) A1is CH; A2is CR7; A3is CH; A4is CH; (59) R7is a group of the formula (IA) shown below:wherein denotes the point of attachment to A1or A2; (60) R7is a group of the formula (IB) shown below:wherein denotes the point of attachment to A1or A2; (61) R8Ais hydrogen, (1-4C)alkyl, hydroxy-(1-2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6- membered cycloalkyl, aryl, 4- to 6-membered heterocyclyl, heteroaryl, 4- to 6-membered cycloalkyl-(1-2C)alkyl, aryl-(1-2C)alkyl, 4- to 6-membered heterocyclyl-(1-2C)alkyl, heteroaryl-(1-2C)alkyl or 8- to 10-membered carbocyclyl, wherein any alkyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, (4- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl. (62) R8Ais hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxymethyl, hydroxyethyl, methoxymethane, methoxyethane, 5- or 6-membered cycloalkyl, phenyl, 5- or 6-membered nitrogen-containing heterocyclyl, 5- or 6-membered oxygen-containing heterocyclyl, 5- or 6-membered nitrogen-containing heteroaryl, 5- or 6-membered oxygen- containing heteroaryl, 5- or 6-membered cycloalkyl-(1-2C)alkyl, phenyl-(1-2C)alkyl, 5- or 6- membered nitrogen-containing heterocyclyl-(1-2C)alkyl, 5- or 6-membered oxygen- containing heterocyclyl-(1-2C)alkyl, 5- or 6-membered nitrogen-containing heteroaryl-(1- 2C)alkyl, 5- or 6-membered oxygen-containing heteroaryl-(1-2C)alkyl or 8- to 10-membered carbocyclyl, wherein any alkyl moiety present in R8Ais optionally substituted by one or two substituents independently selected from chloro, fluoro, hydroxy, cyano, oxo, methoxy, ethoxy, (5- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one or two substituents independently selected from chloro, fluoro, hydroxy, cyano, oxo, methyl, ethyl, methoxy, ethoxy, CHF2, CF3, (5- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; (63) R8Ais hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxyethyl, methoxyethane, phenyl, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1-2C)alkyl, pyridine-(1-2C)alkyl, morpholine-(1-2C)alkyl, tetrahydropyran-(1- 2C)alkyl, or dihydroindene, wherein any alkyl moiety present in R8Ais optionally substituted by one substituent selected from chloro, fluoro, hydroxy, methoxy or phenyl;wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one substituent selected from chloro, fluoro, hydroxy, methyl, methoxy or phenyl; (64) R8Ais hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxyethyl, methoxyethane, phenyl, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1-2C)alkyl, pyridine-(1-2C)alkyl, morpholine-(1-2C)alkyl, tetrahydropyran-(1- 2C)alkyl, or dihydroindene, wherein any heterocyclyl or heteroaryl moiety present in R8Ais optionally substituted by methyl (65) R8Ais hydrogen, methyl, ethyl, hydroxyethyl, methoxyethane, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1C)alkyl, pyridine-(1-2C)alkyl, morpholine-(2C)alkyl, tetrahydropyran-(2C)alkyl, or dihydroindene, wherein any heterocyclyl or heteroaryl moiety present in R8Ais optionally substituted by methyl; (66) R8is a group of the formula (IA-I) shown below:(IA-I) wherein denotes the point of attachment; (67) R8Band R8Dare each independently selected from the group consisting of hydrogen, halo, (1-2C)alkyl, (4-6C)cycloalkyl, (4-6C)cycloalkyl-(1-2C)alkyl and -C(O)NR8FR8G, wherein R8Fand R8Gare each independently selected from hydrogen or (1-2C)alkyl; wherein any alkyl moiety present in R8Band / or R8Dis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any cycloalkyl moiety present in R8Band / or R8Dis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; (68) R8Band R8Dare each independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, and -C(O)NH2; wherein any alkyl moiety present in R8Band / or R8Dis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, methoxy, (5-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; andwherein any cycloalkyl moiety present in R8Band / or R8Dis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, methyl, methoxy, CH2F, CF3, (5-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; (69) R8Band R8Dare each independently selected from the group consisting of hydrogen, fluoro, chloro or methyl; (70) R8Band R8Dare both hydrogen; (71) R8is a group of the formula (IA-Ia) shown below:(IA-Ia) wherein denotes the point of attachment; (72) R8Cis selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, [(1-4C)alkyl]amino, di-[(1- 4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1- 4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1- 4C)alkoxy-(1-4C)alkyl, 4- to 6-membered cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, 4- to 6- membered heterocyclyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, NR8CAR8CB(wherein R8CAand R8CBare each independently selected from hydrogen and (1-3C)alkyl), (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any phenyl or 5- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1- 2C)alkoxy, (4-6C)cycloalkyl or (4-6C)cycloalkoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, NR8CCR8CD(wherein R8CCand R8CDare each independently selected from hydrogen and (1-4C)alkyl), (4- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any phenyl or 5- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4- 6C)cycloalkyl or (4-6C)cycloalkoxy;(73) R8Cis selected from hydrogen, fluoro, chloro, bromo, (1-3C)alkyl, (1-3C)alkoxy, [(1- 3C)alkyl]amino, di-[(1-3C)alkyl]amino, amino-(1-3C)alkyl, [(1-3C)alkyl]amino-(1-3C)alkyl, di- [(1-3C)alkyl]amino-(1-3C)alkyl, [(1-3C)alkyl][(3-5C)cycloalkyl]amino-(1-3C)alkyl, hydroxy-(1- 3C)alkyl, (1-3C)alkoxy-(1-3C)alkyl, 4- to 6-membered cycloalkyl-(1-3C)alkyl, aryl-(1-3C)alkyl, 4- to 6-membered heterocyclyl-(1-3C)alkyl or heteroaryl-(1-3C)alkyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, (1- 2C)alkoxy, NH2, (5-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any phenyl or 5- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl or methoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, NH2, (5- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any phenyl or 5- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl or methoxy (74) R8Cis selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, [(1- 2C)alkyl]amino, di-[(1-2C)alkyl]amino, amino-(1-2C)alkyl, [(1-2C)alkyl]amino-(1-2C)alkyl, di- [(1-2C)alkyl]amino-(1-2C)alkyl, [(1-2C)alkyl][(3-4C)cycloalkyl]amino-(1-2C)alkyl, hydroxy-(1- 2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6-membered cycloalkyl-(1-2C)alkyl, aryl-(1-2C)alkyl, 4- to 6-membered nitrogen-containing heterocyclyl-(1-2C)alkyl or nitrogen-containing heteroaryl-(1-2C)alkyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methoxy, NH2, (5- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, NH2, (5- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; (75) R8Cis selected from hydrogen, methyl, methoxy, [(1-2C)alkyl]amino, di-[(1- 2C)alkyl]amino, amino-(1-2C)alkyl, [(1-2C)alkyl]amino-(1-2C)alkyl, di-[(1-2C)alkyl]amino-(1- 2C)alkyl, [(1-2C)alkyl][(3-4C)cycloalkyl]amino-(1-2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6- membered cycloalkyl-(1-2C)alkyl, phenyl-(1-2C)alkyl, 4- to 6-membered nitrogen-containing heterocyclyl-(1-2C)alkyl or nitrogen-containing heteroaryl-(1-2C)alkyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy or NH2; andwherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, methyl, methoxy, CHF2, CF3or NH2; (76) R8Cis selected from hydrogen, methyl, [(1-2C)alkyl]amino, di-[(1-2C)alkyl]amino, amino- (1-2C)alkyl, [(1-2C)alkyl]amino-(1-2C)alkyl, di-[(1-2C)alkyl]amino-(1-2C)alkyl, [(1- 2C)alkyl][(3-4C)cycloalkyl]amino-(1-2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6-membered nitrogen-containing heterocyclyl-(1-2C)alkyl or nitrogen-containing heteroaryl-(1-2C)alkyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy or NH2; and wherein any alkoxy, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy or NH2;(77) R8cis selected from hydrogen, methyl, -CH2-NR8C1R8C2, -CH2-N(R8C1)(3C)cycloalkyl, NR8C1R8C2, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6-membered nitrogen-containing heterocyclyl-(1- 2C)alkyl or nitrogen-containing heteroaryl-(1-2C)alkyl, wherein R8C1and R8C2are each independently selected from hydrogen, methyl and ethyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy or NH2; and wherein any alkoxy, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy or NH2; (78) R8cis selected from hydrogen, methyl, -CH2-NH2, -CH2-NMe2, -CH2-Net2, -CH2-N(Me)Et, CH2-N(Me)cyclopropyl, -NH2, -Nme2, (1-2C)alkoxy-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, morpholine-(1-2C)alkyl or azetidine-(1-2C)alkyl, wherein any alkoxy, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with two substituents independently selected from fluoro, chloro, hydroxy or methyl (79) R8cis selected from hydrogen, methyl, -CH2-Nme2, -CH2-N(Me)Et, methoxymethane, pyrrolidine-(1C)alkyl, morpholine-(1C)alkyl or azetidine-(1C)alkyl, wherein any alkoxy, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with two substituents independently selected from fluoro or methyl; (80) R8cis selected from hydrogen, methyl, -CH2-Nme2, -CH2-N(Me)Et, methoxymethane, pyrrolidine-(1C)alkyl, morpholine-(1C)alkyl or azetidine-(1C)alkyl, wherein any heterocyclyl moiety present in R8Cis optionally substituted with two fluoro; (81) R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl,wherein any 5-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1- 3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; (82) R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a 5-membered heterocyclyl, wherein any 5-membered heterocyclyl is optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy, CHF2or CF3;C (83) R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a 5-membered heterocyclyl; (84) R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a pyrrolidone ; (85) R12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R12is –(CHRp)f-Z12, wherein Rp is hydrogen or methyl; f is 0 or 1; and Z12is -OR20, -NR21R22, -C(O)NR21R22or -NR23C(O)R24; wherein R20is (1-3C)alkyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRq)e-(3- 6C)cycloalkyl, -(CHRq)e-phenyl, -(CHRq)e-[4 to 6-membered heterocyclyl] or –(CHRq)e-[5 or 6 membered heteroaryl], wherein Rq is hydrogen or methyl; and e is 0 or 1; R21and R22are each independently selected from hydrogen, (1-4C)alkyl, (2-4C)alkanoyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRr)d-(3- 6C)cycloalkyl, -(CHRr)d-phenyl, -(CHRr)d-[4 to 6-membered heterocyclyl] or –(CHRr)d-[5 or 6 membered heteroaryl], wherein Rr is hydrogen or methyl; and d is 0 or 1; or R21and R22are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; R23is hydrogen or (1-2C)alkyl; R24is (1-4C)alkyl, (2-4C)alkynyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRs)c-(3-6C)cycloalkyl, -(CHRs)c-phenyl, -(CHRs)c-[4 to 6-membered heterocyclyl] or –(CHRs)c-[5 or 6 membered heteroaryl], wherein Rsis hydrogen or methyl; and c is 0 or 1; wherein each of R20, R21, R22, R23or R24or any ring formed when R21and R22are linked, is optionally substituted with one or two RD; (86) R12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R12is –(CHRp)f-Z12, wherein Rpis hydrogen or methyl; f is 0 or 1; and Z12is -OR20or -NR21R22; wherein R20is (1-3C)alkyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl, R21and R22are each independently selected from hydrogen, (1-2C)alkyl, (2-3C)alkanoyl, (4-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl or a 5 or 6 membered heteroaryl; or R21and R22are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; wherein each of R20, R21or R22or any ring formed when R21and R22are linked, is optionally substituted with one or two RD; (87) R12is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, or R12is -Z12, wherein Z12is -OR20wherein R20is (1-2C)alkyl wherein R20is substituted with one or two RD; (88) R12is selected from chloro, methyl or cyclopropyl; (89) R12is chloro or methyl; (90) R13is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R13is –(CHRo)h-Z13, wherein Ro is hydrogen or methyl; h is 0 or 1; and Z13is -OR25, -NR26R27, -C(O)NR26R27or -NR28C(O)R29;wherein R25is (1-3C)alkyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRn)i-(3- 6C)cycloalkyl, -(CHRn)i-phenyl, -(CHRn)i-[4 to 6-membered heterocyclyl] or –(CHRn)i-[5 or 6 membered heteroaryl], wherein Rnis hydrogen or methyl; and i is 0 or 1; R26and R27are each independently selected from hydrogen, (1-4C)alkyl, (2-4C)alkanoyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRm)j-(3- 6C)cycloalkyl, -(CHRm)j-phenyl, -(CHRm)j-[4 to 6-membered heterocyclyl] or -(CHRm)j-[5 or 6 membered heteroaryl], wherein Rmis hydrogen or methyl; and j is 0 or 1; or R26and R27are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; R28is hydrogen or (1-2C)alkyl; R29is (1-4C)alkyl, (2-4C)alkynyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRl)k-(3- 6C)cycloalkyl, -(CHRl)k-phenyl, -(CHRl)k-[4 to 6-membered heterocyclyl] or -(CHRl)k-[5 or 6 membered heteroaryl], wherein Rl is hydrogen or methyl; and k is 0 or 1; wherein each of R25, R26, R27, R28or R29or any ring formed when R26and R27are linked, is optionally substituted with one or two RD; (91) R13is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R13is -(CHRo)h-Z13, wherein Ro is hydrogen or methyl; h is 0 or 1; and Z13is -OR25or -NR26R27; wherein R25is (1-3C)alkyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl, R26and R27are each independently selected from hydrogen, (1-2C)alkyl, (2-3C)alkanoyl, (4-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl or a 5 or 6 membered heteroaryl,or R26and R27are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; wherein each of R25, R26or R27or any ring formed when R26and R27are linked, is optionally substituted with one or two RD; (92) R13is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, or R13is -Z13, wherein Z13is -OR25; wherein R25is (1-2C)alkyl, wherein R25is substituted with one or two RD(93) R13is selected from chloro, methyl, methoxy or -O-CH2-CH2-N(Me)2; (94) R14is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R14is -(CHRk)m-Z14, wherein Rk is hydrogen or methyl; m is 0 or 1; and Z14is -OR30, -NR31R32, -C(O)NR31R32or -NR33C(O)R34; wherein R30is (1-3C)alkyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRj)o-(3- 6C)cycloalkyl, -(CHRj)o-[4 to 6-membered heterocyclyl] or -(CHRj)o-[5 or 6 membered heteroaryl], wherein Rj is hydrogen or methyl; and o is 0 or 1; R31and R32are each independently selected from hydrogen, (1-4C)alkyl, (2-4C)alkanoyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRi)p-(3-6C)cycloalkyl, - (CHRi)p-[4 to 6-membered heterocyclyl] or -(CHRi)p-[5 or 6 membered heteroaryl], wherein Ri is hydrogen or methyl; and p is 0 or 1; or R31and R32are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; R33is hydrogen or (1-2C)alkyl; R34is (1-4C)alkyl, (2-4C)alkynyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRh)q-(3-6C)cycloalkyl, -(CHRh)q-[4 to 6-membered heterocyclyl] or -(CHRh)q-[5 or 6 membered heteroaryl], wherein Rhis hydrogen or methyl; and q is 0 or 1; wherein each of R30, R31, R32, R33or R34, or any ring formed when R31and R32are linked, is optionally substituted with one or two RD; (95) R14is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R14is -(CHRk)m-Z14, wherein Rkis hydrogen or methyl; m is 0 or 1; and Z14is -OR30or -NR31R32; wherein R30is (1-3C)alkyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6- membered heterocyclyl or a 5 or 6 membered heteroaryl, R31and R32are each independently selected from hydrogen, (1-2C)alkyl, (2-3C)alkanoyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl, or R31and R32are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; wherein each of R30, R31or R32, or any ring formed when R31and R32are linked, is optionally substituted with one or two RD; (96) R14is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, or R14is -Z14, wherein Z14is -OR30; wherein R30is (1-2C)alkyl, wherein R30is substituted with one or two RD; (97) R14is selected from chloro or -O-CH2-CH2-N(Me)2; (98) R14is chloro; (99) Each RDis independently selected from the group consisting of oxo, halo, cyano, hydroxy, (1-2C)alkyl, or a group: -L1-X1-Q1wherein: L1is absent or (1-2C)alkylene;X1is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, - S(O)0-2-, -C(O)-N(R15)- or -NR15-, where each R15is independently selected from hydrogen or (1-2C)alkyl; and Q1is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, or (3-6C)cycloalkyl; (100) Each RDis independently selected from the group consisting of oxo, chloro, fluoro, cyano, hydroxy, methyl, or a group: -L1-X1-Q1wherein: L1is absent or methylene; X1is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, - NH- or NMe-; and Q1is selected from the group consisting of hydrogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, or (3-6C)cycloalkyl; (101) Each RDis independently selected from the group consisting of oxo, chloro, fluoro, hydroxy, methyl, NH2, NHMe or NMe2; (102) A1is N; A2is CR7; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that: A3cannot be CR13when A4is CR14; and A4cannot be CR14when A3is CR13; (103) A1is N; A2is CR7; A3is CH or CR13; A4is CH; (104) A1is N; A2is CR7; A3is CH; A4is CH; (105) A1is CR7; A2is N; A3is selected from CH or CR13; A4is selected from CH or CR14; with the proviso that: A3cannot be CR13when A4is CR14; andA4cannot be CR14when A3is CR13; (106) A1is CR7; A2is N; A3is CH; A4is CH (107) A1is selected from CH, CR7or CR12; A2is selected from CH, CR7or CR12; A3is N; A4is selected from CH or CR14; with the proviso that: one of A1and A2is CR7; (108) A1is CH; A2is CR7; A3is N; A4is selected from CH or CR14; (109) A1is CH; A2is CR7; A3is N; A4is CH; (110) A1is selected from CH, CR7or CR12; A2is selected from CH, CR7or CR12; A3is selected from CH or CR13; A4is N; with the proviso that: one of A1and A2is CR7; (111) A1is CH; A2is CR7; A3is selected from CH or CR13; A4is N.

[0080] Suitably, R2is as defined in numbered paragraph (1). More suitably, R2is as defined in numbered paragraph (2). Even more suitably, R2is as defined in numbered paragraph (3). Still even more suitably, R2is as defined in numbered paragraph (4). Yet still even more suitably, R2is as defined in numbered paragraph (5).

[0081] Suitably, R3is as defined in numbered paragraph (6). More suitably, R3is as defined in numbered paragraph (7). Even more suitably, R3is as defined in numbered paragraph (8). Stilleven more suitably, R3is as defined in numbered paragraph (9). Yet still even more suitably, R3is as defined in numbered paragraph (10).

[0082] Suitably, R4is as defined in numbered paragraph (11). More suitably, R4is as defined in numbered paragraph (12). Even more suitably, R4is as defined in numbered paragraph (13). Still even more suitably, R4is as defined in numbered paragraph (14). Yet still even more suitably, R4is as defined in numbered paragraph (15).

[0083] Suitably, R5is as defined in numbered paragraph (16). More suitably, R5is as defined in numbered paragraph (17). Even more suitably, R5is as defined in numbered paragraph (18). Still even more suitably, R5is as defined in numbered paragraph (19). Yet still even more suitably, R5is as defined in numbered paragraph (20).

[0084] Suitably, R4and R5are as defined in numbered paragraph (21). More suitably, R4and R5are as defined in numbered paragraph (22). Even more suitably, R4and R5are as defined in numbered paragraph (23). Still even more suitably, R4and R5are as defined in numbered paragraph (24). Yet still even more suitably, R4and R5are as defined in numbered paragraph (25). Yet still even more suitably, R4and R5are as defined in numbered paragraph (26). Yet still even more suitably, R4and R5are as defined in numbered paragraph (27).

[0085] Suitably, each RAis as defined in numbered paragraph (28). More suitably, each RAis as defined in numbered paragraph (29). Even more suitably, each RAis as defined in numbered paragraph (30). Still even more suitably, each RAis as defined in numbered paragraph (31). Yet still even more suitably, each RAis as defined in numbered paragraph (32).

[0086] Suitably, X is as defined in numbered paragraph (33). More suitably, X is as defined in numbered paragraph (34). Even more suitably, X is as defined in numbered paragraph (34). Still even more suitably, X is as defined in numbered paragraph (35). Yet still even more suitably, X is as defined in numbered paragraph (36).

[0087] Suitably, Y1is as defined in numbered paragraph (37). More suitably, Y1is as defined in numbered paragraph (38). Even more suitably, Y1is as defined in numbered paragraph (39).

[0088] Suitably, Y2is as defined in numbered paragraph (40). More suitably, Y2is as defined in numbered paragraph (41). Even more suitably, Y2is as defined in numbered paragraph (42).

[0089] Most suitably, Y1and Y2are as defined in numbered paragraph (43).

[0090] Suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (44). More suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (45). Yet more suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (46). Even more suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (47). Yet even more suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (48). Yet still even more suitably, A1, A2, A3 and A4 are as defined innumbered paragraph (49). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (50). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (51). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (52). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (53). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (54). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (55). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (56). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (57). Yet still even more suitably, A1, A2, A3and A4are as defined in numbered paragraph (58).

[0091] Suitably, A1, A2, A3and A4are as defined in numbered paragraph (102). More suitably, A1, A2, A3and A4are as defined in numbered paragraph (103). Yet more suitably, A1, A2, A3and A4 are as defined in numbered paragraph (104).

[0092] Suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (105). More suitably, A1, A2, A3and A4are as defined in numbered paragraph (106).

[0093] Suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (107). More suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (108). Yet more suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (109).

[0094] Suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (110). More suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (111).

[0095] Most suitably, R7is as defined in numbered paragraph (59).

[0096] Suitably, R8Ais as defined in numbered paragraph (61). More suitably, R8Ais as defined in numbered paragraph (62). Even more suitably, R8Ais as defined in numbered paragraph (63). Still even more suitably, R8Ais as defined in numbered paragraph (64). Yet still even more suitably, R8Ais as defined in numbered paragraph (65).

[0097] Suitably, R8is as defined in numbered paragraph (66). Most suitably, R8is as defined in numbered paragraph (71).

[0098] Suitably, R8Band R8Dare as defined in numbered paragraph (67). More suitably, R8Band R8Dare as defined in numbered paragraph (68). Even more suitably, R8Band R8Dare as defined in numbered paragraph (69). Yet still even more suitably, R8Band R8Dare as defined in numbered paragraph (70).

[0099] Suitably, R8Cis as defined in numbered paragraph (72). More suitably, R8Cis as defined in numbered paragraph (73). Even more suitably, R8Cis as defined in numbered paragraph (74). Still even more suitably, R8Cis as defined in numbered paragraph (75). Yet still even moresuitably, R8Cis as defined in numbered paragraph (76). Yet still even more suitably, R8Cis as defined in numbered paragraph (77). Yet still even more suitably, R8Cis as defined in numbered paragraph (78). Yet still even more suitably, R8Cis as defined in numbered paragraph (79). Yet still even more suitably, R8Cis as defined in numbered paragraph (80).

[0100] Suitably, R8Aand R8Dare as defined in numbered paragraph (81). More suitably, R8Aand R8Dare as defined in numbered paragraph (82). Even more suitably, R8Aand R8Dare as defined in numbered paragraph (83). Yet still even more suitably, R8Aand R8Dare as defined in numbered paragraph (84).

[0101] Suitably, R12is as defined in numbered paragraph (85). More suitably, R12is as defined in numbered paragraph (86). Even more suitably, R12is as defined in numbered paragraph (87). Still even more suitably, R12is as defined in numbered paragraph (88). Yet still even more suitably, R12is as defined in numbered paragraph (89).

[0102] Suitably, R13is as defined in numbered paragraph (90). More suitably, R13is as defined in numbered paragraph (91). Even more suitably, R13is as defined in numbered paragraph (91). Still even more suitably, R13is as defined in numbered paragraph (92). Yet still even more suitably, R13is as defined in numbered paragraph (93).

[0103] Suitably, R14is as defined in numbered paragraph (94). More suitably, R14is as defined in numbered paragraph (95). Even more suitably, R14is as defined in numbered paragraph (96). Still even more suitably, R14is as defined in numbered paragraph (97). Yet still even more suitably, R14is as defined in numbered paragraph (98).

[0104] Suitably, RDis as defined in numbered paragraph (99). More suitably, RDis as defined in numbered paragraph (100). Even more suitably, RDis as defined in numbered paragraph (101).

[0105] In a particular group of compounds of the invention, compounds have a structure according to formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I-XVIV) (which are sub-definitions of Formula (I)), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:(I-I) (I-II)(I-IX)(I-XII)(I-XVI)(I-XVIV) wherein R2, R4, R5, X, Y1, Y2, A1, A2, A3, A4, R8, R8A, R8B, R8Cand R8D, and any groups associated therewith, are as defined anywhere herein, in particular any of the numbered paragraphs appearing hereinbefore.

[0106] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16);or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0107] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (4); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0108] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (14); R5is as defined in numbered paragraph (16); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0109] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (19); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0110] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4and R5are as defined in numbered paragraph (26) or (27); RAis as defined in numbered paragraph (28); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0111] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4and R5are as defined in numbered paragraph (26) or (27); RAis as defined in numbered paragraph (32); X is as defined in numbered paragraph (33);Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0112] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (36); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0113] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1and Y2are as defined in numbered paragraph (43); A1, A2, A3 and A4 are as defined in numbered paragraph (44); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0114] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in any one of numbered paragraphs (49)-(52), (55)-(58), (104), (109) or (111); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0115] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); andall other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0116] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (64); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0117] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44);R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (65); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0118] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61); R8is as defined in numbered paragraph (71); R8Cis as defined in numbered paragraph (72); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0119] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21);X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (78); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0120] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in numbered paragraph (44); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (80); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0121] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); or R4and R5are as defined in numbered paragraph (21); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in numbered paragraph (44); R7is as defined in numbered paragraph (59); R8Aand R8Dare as defined in numbered paragraph (84); R8is as defined in numbered paragraph (66); R8Bis as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0122] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in any one of numbered paragraphs (49), (50), (51) or (52); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61);R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); R12is as defined in numbered paragraph (87); R13is as defined in numbered paragraph (92); R14is as defined in numbered paragraph (96); RDis as defined in numbered paragraph (100); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0123] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3 and A4 are as defined in any one of numbered paragraphs (55), (56), (57) or (58); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); R12is as defined in numbered paragraph (87); R13is as defined in numbered paragraph (92); R14is as defined in numbered paragraph (96); RDis as defined in numbered paragraph (100); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0124] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (1); R4is as defined in numbered paragraph (11); R5is as defined in numbered paragraph (16); X is as defined in numbered paragraph (33); Y1is as defined in numbered paragraph (37); Y2is as defined in numbered paragraph (40); A1, A2, A3and A4are as defined in any one of numbered paragraphs (104), (109) or (111); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (61); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (67); R8Cis as defined in numbered paragraph (72); R12is as defined in numbered paragraph (87); R13is as defined in numbered paragraph (92); R14is as defined in numbered paragraph (96); RDis as defined in numbered paragraph (100); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0125] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (3); R4is as defined in numbered paragraph (12); R5is as defined in numbered paragraph (18); or R4and R5are as defined in numbered paragraph (24); X is as defined in numbered paragraph (35); Y1and Y2are as defined in numbered paragraph (43);A1, A2, A3and A4are as defined in numbered paragraph (45); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (63); R8is as defined in numbered paragraph (66); R8Band R8Dare as defined in numbered paragraph (69); R8Cis as defined in numbered paragraph (78); R12is as defined in numbered paragraph (87); R13is as defined in numbered paragraph (92); R14is as defined in numbered paragraph (96); RDis as defined in numbered paragraph (100); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0126] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where present: R2is as defined in numbered paragraph (4); R4is as defined in numbered paragraph (14); R5is as defined in numbered paragraph (19); or R4and R5are as defined in numbered paragraph (27); RAis as defined in numbered paragraph (32); X is as defined in numbered paragraph (36); Y1and Y2are as defined in numbered paragraph (43); A1, A2, A3 and A4 are as defined in numbered paragraph (45); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (65); R8is as defined in numbered paragraph (71); R8Cis as defined in numbered paragraph (80); R12is as defined in numbered paragraph (88); R13is as defined in numbered paragraph (93);R14is as defined in numbered paragraph (97); RDis as defined in numbered paragraph (101); and all other groups are as defined in any one of the numbered paragraphs appearing hereinbefore.

[0127] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R2is as defined in numbered paragraph (5); R4is as defined in numbered paragraph (15); R5is as defined in numbered paragraph (20); X is CH; Y1is -CH2-; Y2is -CH2– or -CH2-CH2-; A1, A2, A3 and A4 are as defined in numbered paragraphs (52) or (54); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (65); R8is as defined in numbered paragraph (71); and R8Cis as defined in numbered paragraph (80).

[0128] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R2is as defined in numbered paragraph (5); R4is as defined in numbered paragraph (15); R5is hydrogen or methyl; X is CH; Y1is -CH2-; Y2is -CH2-; A1, A2, A3 and A4 are as defined in numbered paragraph (52); R7is as defined in numbered paragraph (59); R8Ais as defined in numbered paragraph (65);R8is as defined in numbered paragraph (71); and R8Cis -CH2-N(CH3)2.

[0129] In an embodiment of the compounds of formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII) or (I- XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: R2is OH; R4is OH; R5is hydrogen; X is CH; Y1is -CH2-; Y2is -CH2-; A1, A2, A3and A4are as defined in numbered paragraph (52); R7is as defined in numbered paragraph (59); R8Ais methyl; R8is as defined in numbered paragraph (71); and R8Cis -CH2-N(CH3)2.

[0130] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R2is as defined in numbered paragraph (3) above. Suitably, R2is as defined in numbered paragraph (4) above. More suitably, R2is as defined in numbered paragraph (5) above.

[0131] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R3is as defined in numbered paragraph (9) above. Suitably, R3is as defined in numbered paragraph (10) above.

[0132] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R4is as defined in numbered paragraph (13) above. Suitably, R4is as defined in numbered paragraph (14) above. More suitably, R4is as defined in numbered paragraph (15) above.

[0133] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R5is as defined in numbered paragraph (19) above. Suitably, R5is as defined in numbered paragraph (20) above.

[0134] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R4and R5are as defined in numbered paragraph (25) above. Suitably, R4and R5are as defined in numbered paragraph (26) or (27) above. In both of these embodiments, RAis as defined in numbered paragraph (30) above.

[0135] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, X is as defined in numbered paragraph (35) above. Suitably, X is as defined in numbered paragraph (36) above.

[0136] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, Y1and Y2are as defined in numbered paragraph (43) above.

[0137] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, A1, A2, A3 and A4 are as defined in numbered paragraph (48) or (54) above. Suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (52) or (58) above. Suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (104), (109) or (111) above.

[0138] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R7is as defined in numbered paragraph (59) above.

[0139] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R8Ais as defined in numbered paragraph (64) above. Suitably, R8Ais as defined in numbered paragraph (65) above.

[0140] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R8is as defined in numbered paragraph (66) above. Suitably, R8is as defined in numbered paragraph (71) above.

[0141] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R8Band R8Dare as defined in numbered paragraph (69) above. Suitably, R8Band R8Dare as defined in numbered paragraph (70) above.

[0142] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R8Cis as defined in numbered paragraph (78) above. Suitably, R8Cis as defined in numbered paragraph (79) above. More suitably, R8Cis as defined in numbered paragraph (80) above.

[0143] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R8Aand R8Dare as defined in numbered paragraph (83) above. Suitably, R8Aand R8Dare as defined in numbered paragraph (84) above.

[0144] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R12is as defined in numbered paragraph (87) above. Suitably, R12is as defined in numbered paragraph (88) above. More suitably, R12is as defined in numbered paragraph (89) above.

[0145] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R13is as defined in numbered paragraph (92) above. Suitably, R13is as defined in numbered paragraph (93) above.

[0146] In an embodiment of the compounds of formula I or any appropriate sub-definition of formula I (as defined by formulae (I-I) to (I-XVIV)) or by any of the embodiments described in relation to formulae (I-I) to (I-XVIV), or a pharmaceutically acceptable salt, hydrate and / or solvatethereof, R14is as defined in numbered paragraph (96) above. Suitably, R14is as defined in numbered paragraph (97) above. More suitably, R14is as defined in numbered paragraph (98) above. In each of these embodiments, RDis as defined in numbered paragraph (100) above.

[0147] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following: (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(diethylamino)-N-((1-methyl-1H-pyrazol-4- yl)methyl)but-2-enamide; (E)-4-(3,3-Difluoropyrrolidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)but-2- enamide; ((E)-4-(3,3-Difluoroazetidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)but-2- enamide; N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl) acrylamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl)-4-morpholinobut-2-enamide; N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide;N-(2-(5-Chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylacrylamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-4-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylacrylamide; N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)acrylamide; N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)acrylamide; (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-phenethylbut-2-enamide; (E)-N-(2-(2-Chloro-4,6-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3,3-dimethylindoline-5-carbonyl)isoindolin-4-yl)-N- methylbut-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-ethylbut-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2- hydroxyethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(pyridin-4- ylmethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-4- yl)ethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-2- yl)ethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-3- yl)ethyl)but-2-enamide;(E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-2- yl)ethyl)but-2-enamide; E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(tetrahydro-2H- pyran-4-yl)ethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2- methoxyethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(5-Chloro-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-1H-indole-5-carbonyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(5-Bromo-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-(trifluoromethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-Cyano-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-6-(trifluoromethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-Benzoylisoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-2-methoxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2-(Difluoromethyl)-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2-Chloro-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-1H-indazole-5-carbonyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(4-(Difluoromethyl)-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-fluoro-2,4-dihydroxybenzoyl)isoindolin-4-yl)but-2-enamide;(E)-4-(Dimethylamino)-N-(2-(6-hydroxybenzo[d]isoxazole-5-carbonyl)isoindolin-4-yl)but-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(4-Amino-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-ethyl-2,4-dihydroxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(3-Chloro-4-(difluoromethoxy)-6-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(4-(Difluoromethoxy)-2-hydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-N-(2-(3-(tert-Butyl)-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-(trifluoromethyl)benzoyl)isoindolin-4-yl)-N-methylbut- 2-enamide; (E)-N-(2-(3-Chloro-4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut- 2-enamide; N-[2-(2,4-Dihydroxy-5-methyl-benzoyl)isoindolin-4-yl]-N-[2-(4-pyridyl)ethyl]prop-2-enamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-N-(2-(1-methylpyrrolidin-3- yl)ethyl)acrylamide;N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)acrylamide; N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)acrylamide; (E)-N-[2-(2,4-Dihydroxy-5-methyl-benzoyl)isoindolin-4-yl]-4-(dimethylamino)-N-indan-2-yl-but-2- enamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-N-(2-morpholinoethyl)acrylamide; N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)-N-methylacrylamide; (E)-N-[2-(2,4-Dihydroxybenzoyl)isoindolin-4-yl]-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-methylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-fluoro-4-hydroxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-hydroxypicolinoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-methoxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-(trifluoromethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-methoxybut-2-enamide; 1-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-3-(2-(dimethylamino)ethylidene)pyrrolidin- 2-one; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1-methylpiperidin- 4-yl)acrylamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-ethylbut-2- enamide; N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-N-(2-methoxyethyl)acrylamide; N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-N-methylacrylamide;(E)-N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)-5-chloroisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(5-Chloro-2-(2, 4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethyl amino)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)isoindolin-4-yl)- N-methylbut-2-enamide; (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- ethylbut-2-enamide; (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(ethyl(methyl)amino)-N- methylbut-2-enamide; (E)-N-(7-Chloro-2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(7-Chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-N-methyl acrylamide; (E)-N-(5-Chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N- methylbut-2-enamide; (E)-N-(2-(3-Chloro-2-fluoro-4,6-dihydroxybenzoyl) isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(3-Chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-ethylbut- 2-enamide; N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl) isoindolin-4-yl)-N-ethyl acrylamide; N-(2-(3-Chloro-2-fluoro-4,6-dihydroxybenzoyl) isoindolin-4-yl)-N-methylacrylamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-6-(2-(dimethylamino) ethoxy) isoindolin-4-yl)-N- methylacrylamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-2,3-dimethyl-1H-indole-5-carbonyl) isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-2-methyl-1H-indole-5-carbonyl) isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3-methyl-1H-indole-5-carbonyl) isoindolin-4-yl)-N- methylbut-2-enamide;(E)-4-(Dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl) isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-4-methoxy-5-methylbenzoyl)isoindolin-4-yl)-N- methylbut-2-enamide; (E)-N-(2-(3-(tert-Butyl)-2-fluoro-6-hydroxy-5-(hydroxymethyl)benzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(3-(Aminomethyl)-5-(tert-butyl)-6-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-N- methylacrylamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-5-chloroisoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-ethyl-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylbut- 2-enamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(5-Ethyl-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; (E)-N-(2-(3-(tert-Butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(3-(tert-Butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl) isoindolin-4-yl)-N-methyl acrylamide; (E)-N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(5-Chloro-2-(5-chloro-2-hydroxy-4-methoxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N- methylbut-2-enamide;(E)-N-(5-Chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(4-Fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(6-Hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(6-Hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl) isoindolin-4-yl)-N-methyl acrylamide; N-(6-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N- methylacrylamide; N-(7-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin- 2-yl)-N-methylacrylamide; N-(6-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin- 3-yl)-N-methylacrylamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-4-fluoro-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-enamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(6-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) acrylamide;(E)-N-(2-(3-Chloro-6-hydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(6-(5-(tert-Butyl)-2-hydroxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-(dimethylamino)- N-methylbut-2-enamide; (E)-N-(5-Chloro-2-(4-hydroxy-3-isopropylbenzoyl) isoindolin-4-yl)-4-(dimethylamino) but-2- enamide; (E)-N-(5-Chloro-2-(4-hydroxy-3-isopropylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylacrylamide; N-(6-(2-(Dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-ynamide; (E)-N-(5-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-fluoro-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(3-Chloro-2-fluoro-6-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(5-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-N-methyl acrylamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5-methylisoindolin-4-yl)- N-methylbut-2-enamide; N-(2-(4-Fluoro-2-hydroxy-5-isopropylbenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(6-Chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide;N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(6-(2-(Dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylacrylamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)-N-methylacrylamide; (E)-N-(7-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridin- 2-yl)-N-methylbut-2-enamide; N-(7-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2- yl)-N-methylacrylamide; N-(7-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7- naphthyridin-2-yl)-N-methylacrylamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-N-methylacrylamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1- methylpiperidin-4-yl) acrylamide; (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)-6-methylisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin- 3-yl)-N-methylbut-2-enamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1- methylpyrrolidin-3-yl)acrylamide; ((E)-N-(5-Chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindolin-4-yl)-4- (dimethylamino)but-2-enamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)but-2-enamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3- yl)acrylamide;(E)-N-(2-(3-Chloro-6-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut- 2-enamide; (E)-N-(7-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(7-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-N-methyl acrylamide; (E)-4-(Dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-N-methylbut-2-enamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-ynamide; (E)-N-(5-Chloro-2-(3-chloro-4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(5-Chloro-2-(4-hydroxy-2,3-dimethylbenzoyl) isoindolin-4-yl)-4-(dimethylamino) but-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-3-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- N-methylbut-2-enamide; N-(2-(4-Hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1-methylpiperidin-4- yl)acrylamide; (E)-4-(Dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methoxy-5,6,7,8- tetrahydro-1,6-naphthyridin-3-yl)-N-methylbut-2-enamide; ((E)-4-(Dimethylamino)-N-(6-(4-hydroxy-3-isopropylbenzoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-N-methylbut-2-enamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- N-methylbut-2-enamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3- yl)but-2-ynamide.

[0148] The various functional groups and substituents making up the compounds of the Formula (I), or sub-formulae (I-I) to (I-XVIV), are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 700. More usually, the molecular weight of the compound will be less than 650. More preferably, the molecular weight is less than 600.

[0149] 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.

[0150] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, 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 centre 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”.

[0151] The compounds of this invention may possess one or more asymmetric centres; 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).

[0152] It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess activity.

[0153] 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.

[0154] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (I-I) to (I-XVIV), may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess activity.

[0155] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (I-I) to (I-XVIV), may exhibit polymorphism, and that the invention encompasses all such forms that possess activity.

[0156] Compounds of the Formula (I), or sub-formulae (I-I) to (I-XVIV), may exist in a number of different tautomeric forms and references to compounds of the Formula (I), or sub-formulae (I- I) to (I-XVIV), 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 sub-formulae (I-I) to (I-XVIV). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0157] Compounds of the Formula (I), or sub-formulae (I-I) to (I-XVIV), containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I), or sub- formulae (I-I) to (I-XVIV), 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, 4th Edition, Wiley Interscience. 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.

[0158] The compounds of Formula (I), or sub-formulae (I-I) to (I-XVIV), 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 thepharmacokinetic 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 sub- formulae (I-I) to (I-XVIV), 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 sub-formulae (I-I) to (I-XVIV).

[0159] Accordingly, the present invention includes those compounds of the Formula (I), or sub- formulae (I-I) to (I-XVIV), as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I), or sub- formulae (I-I) to (I-XVIV), 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 sub-formulae (I-I) to (I-XVIV), may be a synthetically-produced compound or a metabolically-produced compound.

[0160] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), 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.

[0161] 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.

[0162] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), 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 sub- formulae (I-I) to (I-XVIV), containing a carboxy group is, for example, a pharmaceuticallyacceptable ester which is cleaved in the human or animal body to produce the parent acid or parent alcohol. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3- 8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1- cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo- 1,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0163] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), 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 sub-formulae (I-I) to (I-XVIV), 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 (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C)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-(1- 4C)alkylpiperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0164] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), 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 (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl]2amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0165] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), 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 (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents onthe phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1-4C)alkyl)piperazin-1- ylmethyl.

[0166] The in vivo effects of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV). As stated hereinbefore, the in vivo effects of a compound of the Formula (I), or sub-formulae (I-I) to (I-XVIV), may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0167] 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.

[0168] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein. Synthesis

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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, orfor example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0178] Resins may also be used as a protecting group.

[0179] The methodology employed to synthesise a compound of Formula (I), or sub-formulae (I-I) to (I-XVIV), will vary depending on the nature of R2, R3, R4, R5, X, Y1, Y2, A1, A2, A3and A4and any substituent groups or subgroups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.

[0180] Once a compound of Formula (I), or sub-formulae (I-I) to (I-XVIV), has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0181] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups R2, R3, R4, R5, X, Y1, Y2, A1, A2, A3and A4may be further reacted to change the nature of the group and provide an alternative compound of Formula (I).

[0182] The resultant compounds of Formula (I), or sub-formulae (I-I) to (I-XVIV), can be isolated and purified using techniques well known in the art.

[0183] The compounds of Formula (I), or sub-formulae (I-I) to (I-XVIV), may be synthesised by the synthetic routes shown in the Examples section below. Biological Activity

[0184] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[0185] Although the pharmacological properties of the compounds of Formula (I) vary with structural change, as expected, the compounds of the invention were found to be active in a PMS2 in vitro assay as described in the Examples section. Pharmaceutical Compositions

[0186] 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 apharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0187] 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).

[0188] 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.

[0189] 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.

[0190] 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.

[0191] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0192] 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 besuitable, 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

[0193] The present invention provides compounds that function as inhibitors of PMS2 activity.

[0194] The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, therefore, have potential therapeutic uses in a variety of disease states in which the inhibition of PMS2 activity is beneficial.

[0195] The present invention therefore provides a method of treating a disease or disorder in which the inhibition PMS2 activity is beneficial 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, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0196] The present invention provides a method of inhibiting PMS2 activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0197] The present invention provides a method of treating a proliferative disorder 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0198] The present invention provides a method of treating cancer 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0199] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0200] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use as a medicament.

[0201] The present invention provides a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein,for use in the treatment of a proliferative disorder.

[0202] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. In a particular embodiment, the cancer is human cancer, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.

[0203] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the inhibition of PMS2 activity.

[0204] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which the inhibition of PMS2 activity is beneficial.

[0205] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative disorder.

[0206] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer.

[0207] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of PMS2 activity.

[0208] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which the inhibition of PMS2 activity is beneficial.

[0209] The term "proliferative disorder", “proliferative condition” and “proliferative disease” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.

[0210] In the above-outlined aspects of the invention, the proliferative disorder is suitably cancer, and the cancer is suitably a human cancer. In particular, the compounds of the present invention will be useful for the treatment of any cancer in which mis-match repair inhibition is beneficial. Any suitable cancer may be targeted (e.g., adenoid cystic carcinoma, adrenal glandtumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith- Wiedemann Syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé Syndrome, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, Carney Complex, central nervous system tumors, cervical cancer, colorectal cancer, Cowden Syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor – GIST, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukamia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li- Fraumeni Syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), Lymphoma (Hodgkin, non-Hodgkin), Lynch Syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia Type 1 & 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus Cancer, nasopharyngeal Cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung or pancreas), neurofibromatosis Type 1 & 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz- Jeghers Syndrome, pheochromocytoma, paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi or soft tissue), skin cancer, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom’s macroglobulinemia, Werner syndrome, Wilms Tumor and xeroderma pigmentosum). Particular cancers of interest include haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-oesophageal cancer, neuroendocrine cancers, osteosarcomas, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, oesophageal cancer, and ovarian cancer.

[0211] The compounds of the present invention may also be used to treat triplet repeat disorders.

[0212] Thus, a further aspect of the present invention provides a method of treating a triplet repeat disorder (e.g., Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs)) 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, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0213] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a triplet repeat disorder. In a particular embodiment, the triplet repeat disorder is selected from the group consisting of Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs).

[0214] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a triplet repeat disorder. In a particular embodiment, the triplet repeat disorder is selected from the group consisting of Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich’s ataxia (FRDA), and spinocerebellar ataxias (SCAs). Routes of Administration

[0215] 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).

[0216] 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 intratumoral, 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

[0217] The compounds of the present invention may be administered as a sole therapy or may involve, in addition to a compound of the invention, conventional surgery or radiotherapy or chemotherapy or a targeted agent. Such chemotherapy or targeted agent may include one or more of the following categories: (i) Antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as, but not limited to, alkylating agents (for example cis-platin, 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 and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecins including irinotecan); (ii) cytostatic agents such as, but not limited to, antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ^-reductase such as finasteride; (iii) anti-invasion agents such as, but not limited to, c-Src kinase family inhibitors 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro- 6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658- 6661), bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function such as, but not limited to, growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as 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 and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors; (v) antiangiogenic agents such as, but not limited to, those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736) and pazopanib (GW 786034); (vi) vascular damaging agents such as, but not limited to, Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, such as, but not limited to, those directed to targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) immunotherapy approaches, including for example cancer vaccines, antibody, viral (oncolytic viruses) and small molecule or cell therapy approaches to increase the immunogenicity of patient tumour cells and / or facilitate a cell mediated anti-tumour response. Such therapies could include, but are not limited to, OX40 agonists, cGAS- STING agonists, ENPP1 inhibitors, CD38 inhibitors, TBK1 inhibitors, A2a receptorantagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, Arginase inhibitors, BTK inhibitors and Bromodomain inhibitors; transduction with microbial vectors of cancer antigens, direct transduction of cancer antigens into antigen presenting cells, treatment with immune cells specific for cancer antigens (e.g., CAR-T), treatment with antibodies, antibody fragments and antibody drug conjugates that enable the immune system to recognise tumour cells.

[0218] 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.

[0219] 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 or solvate thereof, and an anti-tumour agent.

[0220] 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), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, and any one of the anti-tumour agents listed herein above.

[0221] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0222] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.

[0223] 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.

[0224] 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 or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.Combination Therapy with Immune Modulating Treatments Immune checkpoint inhibitors

[0225] Immune checkpoint proteins present on immune cells and / or cancer cells [e.g., CTLA4 (also known as cytotoxic T-lymphocyte-associated protein 4 and CD152), LAG3 (also known as lymphocyte-activation gene 3 and CD223), PD1 (also known as programmed cell death protein 1 and CD279), PD-L1 (also known as programmed death-ligand 1 and CD274), TIM-3 (also known as T-cell immunoglobulin mucin-3) and TIGIT (also known as T-cell Immunoreceptor with Ig and ITIM domains)] are molecular targets that have been found to play an important role in regulating anti-tumour immune responses. Inhibitors of these immune checkpoint proteins (e.g., CTLA4, LAG3, PD1, PD-L1, TIM-3 and / or TIGIT inhibitors) promote an anti-tumour immune response that can be utilised to effectively treat certain forms of cancer. Immune stimulators

[0226] Monoclonal antibodies, bispecific antibodies, recombinant ligands and small molecule therapeutics that bind to stimulatory receptors on immune cells can facilitate an effective anti- tumour response. Such receptors may be involved in cell-to-cell contact for example contact between tumour cell and immune cell or between two types of immunce cells, other receptors may bind to soluble factors that stimulate an immune response. In one such embodiment antibodies, bispecifics, recombindant proteins or small molecule therapeutics can activate stimulatory receptors, including, but not limited to, 4-1BB, OX40, cGAS-STING, CD27, CD40, and DR3 that enhance anti-tumour immunity.

[0227] Modulators of antigen processing may facilitate the presentation of neoantigenic peptides on the cell surface to enhance an effective anti-tumour response. In one such embodiment inhibitors of the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 may stimulate anti-tumour immunity.

[0228] In one aspect, the present invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immune stimulator as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0229] In another aspect, the present invention relates to a use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immune stimulator as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a proliferative disorder.

[0230] In another aspect, the present invention relates to a method of treating a proliferative disorder in a subject in need thereof comprising administering to said subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immune stimulator as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein.

[0231] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a proliferative disorder, wherein the compound, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administeration with an immune checkpoint inhibitor, or immune stimulator, or a pharmaceutically acceptable salt thereof.

[0232] In another aspect, the present invention relates to an immune checkpoint inhibitor or immune stimulator, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder, wherein the immune checkpoint inhibitor is for simultaneous, separate or sequential administeration with a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein.

[0233] In another aspect, the present invention relates to a use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with an immune checkpoint inhibitor or immune stimulator, or a pharmaceutically acceptable salt thereof.

[0234] In another aspect, the present invention relates to a use of an immune checkpoint inhibitor or immune stimulator, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0235] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising adminstering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor or immune stimulator as defined herein, or a pharmaceutically acceptable salt thereof, either sequentially, separately or simultaneously.

[0236] Any immune checkpoint inhibitor or immune stimulator may be used in the combination therapy defined herein.

[0237] In one embodiment, the immune stimulator is selected from a 4-1BB stimulator, a OX40 stimulator, a CD27 stimulator, a CD40 stimulator, and a DR3 stimulator. In another embodimentthe immune checkpoint inhibitor is selected from a PD1-inhibitor, a PD-L1 inhibitor, a LAG3 inhibitor, CTLA-4 inhibitor, a TIM-3 inhibitor and / or a TIGIT inhibitor. In a particular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[0238] PD-1 is a cell surface receptor protein present on immune cells such as T cells. PD-1 plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell activation. The PD-1 protein is an immune checkpoint that guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells).

[0239] PD-1 therefore inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

[0240] PD1 binds two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest as it is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 that boost the immune system are approved or are being developed for the treatment of cancer. Many tumour cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumour activity. This is known as immune checkpoint blockade.

[0241] Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics) and MEDI-0680 (MedImmune).

[0242] Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use against other types of cancer.

[0243] Examples of LAG3 inhibitors include BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781 and LAG525.

[0244] Examples of CTLA-4 inhibitors include MDX-010 / Ipilimumab, AGEN1884, and CP- 675,206 / Tremelimumab.

[0245] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Lilly).

[0246] Examples of TIGIT inhibitors include Tiragolumab (MTIG7192A; RG6058; Genentech / Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207 (Bristol-Myers Squibb), ASP8374 (Astellas Pharma; Potenza Therapeutics).

[0247] In one embodiment, the immune checkpoint inhibitor is selected from BMS- 986016 / Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / Ipilimumab, AGEN1884, and CP-675,206 / Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, MBG453, TSR-022, LY3321367, Tiragolumab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, and / or ASP8374 or a pharmaceutically acceptable salt or solvate thereof. Combination therapy with DNA damage response modulators

[0248] The compounds of the present invention are particularly suited to use in combination with agents that act as DNA damage response modulators, e.g., PARP inhibitors, ATM inhibitors and ATR inhibitors.

[0249] In one aspect, the present invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0250] In another aspect, the present invention relates to a use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating of a proliferative disorder.

[0251] In another aspect, the present invention relates to a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, as defined herein.

[0252] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a proliferative disorder, wherein the compound, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administeration with a DNA damage responsemodulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof.

[0253] In another aspect, the present invention relates to a use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof.

[0254] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising adminstering to a subject in need thereof a therapetuically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, either sequentially, separately or simultaneously.

[0255] Any DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) may be used in the combination therapy defined herein. EXAMPLES

[0256] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims. Abbreviations ACN Acetonitrile Boc tert-Butyloxycarbonyl Bs Broad singlet CPME Cycopentyl methyl ether DAST Diethylaminosulfur trifluoride DCM Dichloromethane Dikis Bis(triphenylphosphine)palladium(II) dichloride DIPEA N,N-Diisopropylethylamine, Hünig’s base DMA N,N-Dimethylacetamide DMAP 4-(Dimethylamino)pyridine DME Dimethyl ether DMF N,N-DimethylformamideDMSO Dimethylsulfoxide. EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc Ethyl acetate Et2O Diethyl ether FA Formic acid h Hours HATU N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide HOBT N-Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography. IPA Isopropyl alcohol LAH Lithium aluminium hydride LCMS Liquid Chromatography-Mass Spectrometry MeOH Methanol MI Molecular Ion min(s) Minutes MW Microwave NCS N-Chlorosuccinimide NMM N-Methylmorpholine NMR Nuclear Magnetic Resonance. PdCl2(PPh3)2 Bis(triphenylphosphine)palladium chloride Pd(dppf)2Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dba)2) Bis(dibenzylideneacetone)palladium RT Retention time or room temperature SFC Supercritical fluid chromatography STAB Sodium triacetoxyborohydride TFAA Trifluoroacetic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran Analytical Methods

[0257] Commercially available starting materials, reagents and dry solvents were used as supplied. Flash chromatography or glass column chromatography was performed using Merck silica gel 230-400 mesh size. Flash chromatography was also performed on combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.Liquid Chromatography-Mass Spectrometry Methods Method A

[0258] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phase A : 0.1% (v / v) formic acid in water (pH = 2.70), Mobile Phase B : 0.1% formic acid (v / v) in water : acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow : 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow : 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 1mL / min; t = 3.5 min (0% A, 100% B) flow : 1 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow : 0.8 mL / min; end of run at t = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120°C and 600°C respectively. Method B

[0259] Waters Acquity with PDA detector and SQ Detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phase A: 5 mM ammonium bicarbonate in water (pH = 7.35), mobile phase B: acetonitrile; mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow : 0.5 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow: 0.5 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 0.7mL / min; t = 3.5 min (0% A, 100% B) flow : 0.7 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow : 0.5 mL / min; end of run at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 min. Mass detection parameter: ionization mode was cycled through positive and negative mode with cone voltage 10 V and 30 V and 3.25 kV capillary voltage, temperature of source and probe were 120°C and 400 °C respectively. Method C

[0260] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: YMC Tri-art C18, 50 x 2 mm, 1.9 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phase A : 0.1% (v / v) formic acid in water (pH = 2.70), Mobile Phase B : 0.1% formic acid (v / v) in water : acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow : 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow : 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 1mL / min; t = 3.5 min (0% A, 100% B) flow : 1 mL / min; gradient to t = 3.51min (97% A, 3% B) flow : 0.8 mL / min; end of run at t = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120°C and 600°C respectively. Method D

[0261] Waters Acquity UPLC with quaternary solvent manager, with PDA detector and SQ detector, column: X-Bridge BEH C18, 50*2.1 mm,2.5 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phase A : 0.1% (v / v) Formic acid in water (pH = 2.70), mobile phase B : 0.1% (v / v) formic acid in water : acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow : 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow : 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 1mL / min; t = 3.5 min (0% A, 100% B) flow : 1 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow : 0.8 mL / min; end of run at t = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameter: ESI capillary probe, ionization mode cycled through positive and negative modes with cone voltage 10 V and 30V and 0.8 kV capillary voltage, temperature of source and probe were 120°C and 400°C respectively. Method E

[0262] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: Welch Xtimate C18, 50*2.1 mm, 1.8 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phase A : 0.1% (v / v) formic acid in water (pH = 2.70), Mobile Phase B : 0.1% formic acid (v / v) in water : acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow : 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow : 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 1mL / min; t = 3.5 min (0% A, 100% B) flow : 1 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow : 0.8 mL / min; end of run at t = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120°C and 600°C respectively. Method F

[0263] Waters Acquity UPLC with PDA detector and SQ Detector, column: Welch-Xtimate,C18 4.6*50mm,5 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phaseA: 5 mM ammonium bicarbonate in water (pH = 7.35), mobile phase B: acetonitrile; mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow : 0.5 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow: 0.5 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 0.7mL / min; t = 3.5 min (0% A, 100% B) flow : 0.7 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow : 0.5 mL / min; end of run at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 min. Mass detection parameter: ionization mode was cycled through positive and negative mode with cone voltage 10 V and 30 V and 3.25 kV capillary voltage, temperature of source and probe were 120°C and 400 °C respectively. Method G

[0264] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: X-Bridge C18 2.1*50mm3.5 micron, column temperature: 35°C, auto sampler temperature: 5°C, mobile phase A: 5 mM ammonium bicarbonate in water (pH = 7.35), mobile phase B: acetonitrile; mobile phase gradient details: t = 0 min (97% A, 3% B) flow : 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow : 0.5 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow: 0.5 mL / min; gradient to t = 3 min (0% A, 100% B) flow : 0.7mL / min; t = 3.5 min (0% A, 100% B) flow : 0.7 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow : 0.5 mL / min; end of run at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120°C and 600°C respectively. Method H

[0265] Waters 996 Photodiode Array Detector equipped with Waters Micromass ZQ detector, column: XTIMATE C185µm 4.6*150mm, Column temperature: 35°C, Auto sampler temperature: 15°C, Mobile Phase A: 5mM Ammonium Acetate and 0.1 % Formic acid (pH =3.50) in Milli Q water, Mobile Phase B: Methanol. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- PDA. Mass parameter: Probe: ESI, Mode of Ionisation: Positive and Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV, Extractor Voltage:-2 V, Rf Lens:- 0.1 V, Temperature of source:-120°C,Temperature of Probe:- 400 °C,Cone Gas Flow:- 100 L / Hr, Desolvation Gas flow:-800 L / Hr.Method I

[0266] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: 30°C, Auto sampler temperature: 15°C,Mobile Phase A : 0.1 % Formic acid in Milli Q water (pH= 2.70), Mobile Phase B : 0.1%Formic acid in Milli Q water : Acetonitrile (10:90), Mobile phase gradient details: T = 0 min (97% A, 3% B) flow : 0.8 mL / min; T = 0.75 min (97% A, 3% B) flow : 0.8 mL / min; gradient to T = 2.7 min (2% A, 98% B) flow : 0.8 mL / min; gradient to T = 3 min (0% A, 100% B) flow : 1mL / min; T = 3.5 min (0% A, 100% B) flow : 1 mL / min; gradient to T= 3.51 min (97% A, 3% B) flow : 0.8 mL / min; end of run at T = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, Run Time:- 4 min. UV Detection Method: - PDA Mass parameter: Probe:-ESI, Mode of Ionisation :- positive and negative, Cone voltage :-10V and 30V, capillary voltage:- 0.8 KV, Extractor Voltage:- 1KV, Rf Lens:- 0.1,Temperature of source:-120°C,Temperature of Probe:- 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method J

[0267] Waters 996 Photodiode Array Detector equipped with Waters Micromass ZQ detector, column: XTIMATE C185µm 4.6*150mm, Column temperature: 60°C, Auto sampler temperature: 15°C, Mobile Phase A: 5mM Ammonium Acetate and 0.1 % Formic acid (pH =3.50) in Milli Q water, Mobile Phase B: Methanol. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- PDA. Mass parameter: Probe: ESI, Mode of Ionisation: Positive and Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV, Extractor Voltage:-2 V, Rf Lens:- 0.1 V, Temperature of source:-120°C,Temperature of Probe:- 400 °C,Cone Gas Flow:- 100 L / Hr, Desolvation Gas flow:-800 L / Hr. Method K

[0268] Agilent 1260 Infinity-II DAD Detector equipped with MASS detector Agilent G6125C (LC / MSD), column: XTIMATE C185µm 4.6*150mm, Column temperature: 35°C, Auto sampler temperature: 15°C, Mobile Phase A: 5mM Ammonium Acetate and 0.1 % Formic acid (pH =3.50) in Milli Q water, Mobile Phase B: Methanol. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- DAD. Massparameter: Probe: MMI, Mode of Ionisation: (ESI) Positive and Negative, Fragment voltage :-30 and 70 V, capillary voltage:- 3000 V, Gas temperature of source:-325°C,Temperature of Vaporizer:- 225 °C, Gas Flow:- 12 L / min, Nebulizer:- 50 Method L

[0269] Agilent 1260 Infinity-II DAD Detector equipped with MASS detector Agilent G6125C (LC / MSD), column: XTIMATE C185µm 4.6*150mm, Column temperature: 60°C, Auto sampler temperature: 15°C, Mobile Phase A: 5mM Ammonium Acetate and 0.1 % Formic acid (pH =3.50) in Milli Q water, Mobile Phase B: Methanol. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- DAD. Mass parameter: Probe: MMI, Mode of Ionisation: (ESI) Positive and Negative, Fragment voltage :-30 and 70 V, capillary voltage:- 3000 V, Gas temperature of source:-325°C,Temperature of Vaporizer:- 225 °C, Gas Flow:- 12 L / min, Nebulizer:- 50 Method M

[0270] Waters 996 Photodiode Array Detector equipped with Waters Micromass ZQ detector, column: XTIMATE C185µm 4.6*150mm, Column temperature: 35°C, Auto sampler temperature: 15°C, Mobile Phase A: 0.05% Trifluoro acetic acid (pH =3.50) in Milli Q water, Mobile Phase B: Acetonitrile. Mobile phase gradient details: T = 0 min (100% A, 00% B); T = 7.0min (50% A, 50% B); gradient to T = 9.0 min (00% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 00% B); end of run at T = 17 min (100% A, 00% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- PDA. Mass parameter: Probe: ESI, Mode of Ionisation: Positive and Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV, Extractor Voltage:-2 V, Rf Lens:- 0.1 V, Temperature of source:-120°C,Temperature of Probe:- 400 °C,Cone Gas Flow:- 100 L / Hr, Desolvation Gas flow:-800 L / Hr. Method N

[0271] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic Acid in Acetonitrile, Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35%B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time: 4 min. UV Detection Method:PDA Mass parameter: Probe:ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method O

[0272] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 5mM Ammonium Bicarbonate in Milli Q water, Mobile Phase B : Acetonitrile, Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35% B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time:- 4 min. UV Detection Method: PDA Mass parameter: Probe:ESI, Mode of Ionisation :positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method P

[0273] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default Method Q

[0274] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (100% A, 0% B); T = 7.0 min (50% A, 50% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 0% B); end of run at T = 17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default Method R

[0275] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (50% A, 50% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (50% A, 50% B); end of run at T = 17 min (50% A, 50% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method S

[0276] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 0.05% Trifluoro Acetic Acid in Milli Q water, Mobile Phase B: Acetonitrile, Mobile phase gradient details: T = 0 min (100% A, 0% B); T = 7.0 min (50% A, 50% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 0% B); end of run at T = 17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default.Method T

[0277] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDa detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic Acid in Acetonitrile, Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35% B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time: 4 min. UV Detection Method:PDA Mass parameter: Probe:ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method U

[0278] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: 800C Auto sampler temperature: 150C, Phase A : 5mM Ammonium Bicarbonate in Milli Q water, Mobile Phase B : Acetonitrile,, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method V

[0279] Agilent 1260 Infinity-II DAD Detector equipped with MASS detector Agilent G6125C (LC / MSD), column: XTIMATE C185µm 4.6*150mm, Column temperature: 60°C, Auto sampler temperature: 15°C, Mobile Phase A : 5mM Ammonium Bicarbonate in Milli Q water, Mobile Phase B : Acetonitrile,. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- DAD. Mass parameter: Probe: MMI, Mode of Ionisation: (ESI) Positive and Negative, Fragment voltage :-30 and 70 V, capillary voltage:-3000 V, Gas temperature of source:-325°C,Temperature of Vaporizer:- 225 °C, Gas Flow:- 12 L / min, Nebulizer:- 50 Method W

[0280] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient Auto sampler temperature: 150C, Phase A : 5mM Ammonium Bicarbonate in Milli Q water, Mobile Phase B : Acetonitrile,, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method X

[0281] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 0.05% Trifluoro Acetic Acid in Milli Q water, Mobile Phase B: Acetonitrile, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Run Time: 17 min. Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method Y

[0282] Waters 996 Photodiode Array Detector equipped with Waters Micromass ZQ detector, column: XTIMATE C185µm 4.6*150mm, Column temperature: 35°C, Auto sampler temperature: 15°C, Mobile Phase A: 0.05% Trifluoro acetic acid (pH =3.50) in Milli Q water, Mobile Phase B: Acetonitrile. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B). Flow rate:- 1.0 mL / min, RunTime:- 17 min, UV Detection Method:- PDA. Mass parameter: Probe: ESI, Mode of Ionisation: Positive and Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV, Extractor Voltage:- 2 V, Rf Lens:- 0.1 V, Temperature of source:-120°C,Temperature of Probe:- 400 °C,Cone Gas Flow:- 100 L / Hr, Desolvation Gas flow:-800 L / Hr. Method Z

[0283] Waters Acquity UPLC- H Class equipped with PDA and attached with SQd detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 3.0 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default Method A1

[0284] Waters Acquity UPLC- H Class equipped with PDA and attached with SQd detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (100% A, 0% B); T = 7.0 min (50% A, 50% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 0% B); end of run at T = 17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 3.0 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default Method A2

[0285] Waters Acquity UPLC equipped with PDA and attached with SQd detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A: 0.05% Trifluoro acetic acid (pH =3.50) in Milli Q water, Mobile Phase B: Acetonitrile. Mobile phase gradient details: T = 0 min (100% A, 0% B); T = 7.0min (50% A, 50% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 0% B); end of run at T = 17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 3.0 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default Method A3

[0286] Waters Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase: 5mM ammonium bicarbonate in water (pH = 7.35), mobile phase B: Acetonitrile. Mobile phase gradient details: T = 0 min (100% A, 0% B); T = 7.0 min (50% A, 50% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 0% B); end of run at T = 17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default. Method A4

[0287] Waters Acquity UPLC- H Class equipped with PDA and attached with SQd detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic Acid in Acetonitrile, Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35% B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time: 4 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 3.0 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default Method A5

[0288] Waters Acquity UPLC equipped with PDA and attached with SQd detector,column: X- Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C,Mobile Phase A : 5mM ammonium bicarbonate in water (pH = 8.0), Mobile Phase B : Acetonitrile. Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35% B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time: 4 min.UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 3.0 KV, Extractor Voltage: 1KV, Rf Lens: 0.1,Temperature of source: 120°C,Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default LC-Method 1

[0289] UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrupole UPLC- MS spectrometer using an Acquity UPLC HSS Shield RP181.7 µm 100 x 2.1 mm (Plus guard cartridge), maintained at 40 ˚C column being initially held at 5% Acetonitrile (Far UV grade) with 0.1% (V / V) formic acid / water (High purity via PureLab Option unit) with 0.1% formic acid for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL / min). LC-Method 2

[0290] UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrupole UPLC- MS spectrometer using an Acquity UPLC BEH Shield RP181.7 µm 100 x 2.1 mm (Plus guard cartridge), maintained at 40 ˚C column being initially held at 5% acetonitrile / water (with 10 mM ammonium bicarbonate) for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL / min). LC-Method 3

[0291] UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrupole UPLC- MS spectrometer using an Acquity UPLC BEH C181.7um 100 x 2.1mm (Plus guard cartridge), maintained at 40°C column being initially held at 5% Acetonitrile (Far UV grade) with 0.1% (V / V) formic acid / Water (High purity via PureLab Option unit) with 0.1% formic acid for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL / min).LC-Method 4

[0292] UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrupole UPLC- MS spectrometer using an Acquity UPLC BEH C181.7um 100 x 2.1mm (Plus guard cartridge), maintained at 40°C column being initially held at 5% acetonitrile / water (with 0.1% v / v ammonium hydroxide) for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL / min). Analytical HPLC Methods Method B

[0293] Machine Details: - Agilent 1260 Series with PDA detector, Column temperature: 25 ˚C, Auto sampler temperature: 25 ˚C, Mobile Phase A: 0.05% Trifluoro acetic acid in Milli Q water (pH= 2.1), Mobile Phase B: Acetonitrile (100%).

[0294] Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- PDA. Method C

[0295] Machine Details: - Water alliance e2695 with 2998 PDA detector, Column temperature: 25 ˚C, Auto sampler temperature: 25 ˚C,Mobile Phase A: 0.1% ammonium hydroxide solution in HPLC water Mobile Phase B : Acetonitrile (100%).

[0296] Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- PDA. Method D

[0297] Machine Details: Shimadzu i-series LC-2050C with PDA detector, Column temperature: 25 ˚C, Auto sampler temperature: 25 ˚C, Mobile Phase A: 0.05% Trifluoro acetic acid in Milli Q water (pH= 2.1), Mobile Phase B: Acetonitrile (100%).

[0298] Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate:- 1.0 mL / min, Run Time:- 17 min, UV Detection Method:- PDA NMR

[0299] 1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad. Purification methods Preparative reverse-phase HPLC conditions

[0300] Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl at 10 µm 19 × 150 mm or Waters CSH Phenyl Hexyl, 19 × 150, 5 µm column unless otherwise stated. Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The modifiers used under acidic / basic conditions were formic acid or TFA (0.1% V / V) and ammonium bicarbonate (10 mM) respectively. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD).

[0301] Below is a list of methods and conditions used for preparative reverse phase HPLC purifications. Preparative HPLC Conditions Method Sunfire C1819 x 150 mm, 10 µm 5-60% ACN / H2O (10 mM NH4CO3), prep-LC-1 20 mL / min, room temperatureLuna Phenyl-Hexyl 21.2 x 150 mm, 10 µm 20-80% MeOH / H2O (0.1% prep-LC-2 FA), 20 mL / min, room temperature Sunfire C1819 x 150 mm, 10 µm 5-60% ACN / H2O (0.1% FA), 20 prep-LC-3 mL / min, room temperature Luna Phenyl-Hexyl 21.2x150 mm, 10 µm 5-60% MeOH / H2O (0.1% prep-LC-4 FA), 20 mL / min, room temperature Xbridge Phenyl 19 x 150 mm, 10 µm 20-80% MeOH / H2O (10 mM prep-LC-5 NH4CO3), 20 mL / min, room temperature Sunfire C1819 x 150 mm, 10 µm 35-45% MeOH / H2O (0.1% TFA), 20 prep-LC-6 mL / min, room temperature Xbridge Phenyl 19 x 150 mm, 10 µm 5-60% MeOH / H2O (10 mM prep-LC-7 NH4CO3), 20 mL / min, room temperature Sunfire C1819 x 150 mm, 10 µm 5-60% ACN / H2O (0.1% FA), 20 prep-LC-8 mL / min, room temperature Sunfire C1819 x 150 mm, 10 µm 20-80% ACN / H2O (0.1% FA), 20 Prep-LC-9 mL / min, room temperature Luna Phenyl-Hexyl 3 x 50 mm, 3 µm 5-95% MeOH / H2O (0.1% FA), Prep-LC-10 1.7 mL / min, room temperature Sunfire C183 x 50 mm, 3 µm 5-95% ACN / H2O (10 mM NH4CO3), 1.7 Prep-LC-11 mL / min, room temperature Sunfire C1819x150 mm, 10 µm 5-60% ACN / H2O (0.1% TFA), 20 Prep-LC-12 mL / min, room temperature Luna Phenyl-Hexyl 21.2x150 mm, 10 µm 40-100% MeOH / H2O (0.1% Prep-LC-13 FA), 20 mL / min, room temperature Chiral Supercritical Fluid Chromatography (SFC) separation protocol

[0302] The enantiomeric separation of compounds was achieved by Supercritical Fluid Chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with Stacked Injection Module). The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol or isopropanol solvent systems under un-modified or basic conditions. The standard SFC method used was modifier, CO2, 100 mL / min, 120 Bar backpressure, 40 ˚C column temperature. The modifier used under basic conditions was diethylamine (0.1% V / V). The modifier used under acidic conditions was either formic acid (0.1% V / V) or TFA (0.1% V / V). The SFC purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered at a threshold collectionvalue, typically 260 nm. Collected fractions were analysed by SFC (Waters / Thar SFC systems with Waters SQD). The fractions that contained the desired product were concentrated by vacuum centrifugation.

[0303] Below is a list of SFC methods and conditions used to resolve enantiomers or to determine enantiomeric purity. SFC method Conditions for chiral resolution WATERS VIRIDIS 2-EP 20 x 250 mm, 5 µm 15-25% MeOH (0.1% NH4OH) / CO2, SFC-1 100 mL / min, 120 bar, 40° C, DAD 250 nm WATERS VIRIDIS 2-EP 20 x 250 mm, 5 µm 10-20% MeOH (0.1% NH4OH) / CO2, SFC-2 100 mL / min, 120bar, 40 ˚C, DAD 250 nm WATERS TORUS DEA 20 x 150 mm, 5 µm 20-30% MeOH (0.1% NH4OH) / CO2, SFC-3 100 mL / min, 120 bar, 40 ˚C, DAD 270 nm Preparation of compounds Example 1: (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide Step 1: (3-Chloro-4,6-dihydroxy-2-methylphenyl)(4-(methylamino)isoindolin-2-yl)methanone

[0304] To a stirred solution of 3-chloro-4,6-dihydroxy-2-methylbenzoic acid (Intermediate B) (0.4 g, 1.97 mmol, 1 eq.) in DMF (4 mL) were added EDC.HCl (0.56 g, 2.96 mmol, 1.5 eq.) and HOAT (0.26 g, 1.97 mmol, 1 eq.) at 0 ˚ C. N-Methylisoindolin-4-amine hydrochloride (Intermediate A) (0.43 g, 2.36 mmol, 1.2 eq.) and N-methyl morpholine (0.99 g, 9.87 mmol, 5 eq.) were added and the mixture was stirred at 0˚C for 10 mins and then at room temperature for 30 mins. The resulting mixture was poured into ice cold water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by chromatography on silica (product eluted in 4% MeOH in DCM) to afford the title compound as an off-white solid (0.3 g, Yield: 22.8%).

[0305] 1H NMR (DMSO-d6, 400 MHz): δ 2.13 (s, 3H), 2.61 - 2.72 (dd, J= 4 Hz, 3H), 4.10 - 4.47 (m, 2H), 4.56 (s, 1H), 4.70 (s, 1H), 5.34 - 5.52 (dd, J= 4 Hz, 1H, D2O exchangeable), 6.34 - 6.40 (m, 1H), 6.44 -6.48 (m, 2H), 7.06 - 7.13 (m, 1H), 9.75 (d, J= 8 Hz, 1H, D2O exchangeable), 10.10 (d, J= 4 Hz, 1H, D2O exchangeable).

[0306] LCMS (Method A): 1.482 min, 1.592 min, MS: ES+ 332.8 (M+1). Step 2: (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide

[0307] Performed in 2 parallel batches, each of 0.15 g scale: To a stirred solution of (E)-4- (dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) (0.15 g, 0.90 mmol, 1.0 eq.) in DMF (1.5 mL) were added (3-chloro-4,6-dihydroxy-2-methylphenyl)(4- (methylamino)isoindolin-2-yl)methanone (Step 1) (0.15 g, 0.45 mmol, 0.5 eq.) and DCC (0.28 g, 1.35 mmol, 1.5 eq.) and the reaction mixture was heated to 150 ˚C using microwave irradiation for 15 mins. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by Prep. HPLC to afford the title compound (0.04 g, Yield: 10%).

[0308] High temperature1H NMR (DMSO-d6, 400 MHz, 348K): δ 2.10 - 2.15 (s, 3H), 2.63 - 2.83 (m, 6H), 3.10 (s, 3H), 3.73 - 3.77 (m, 2H), 4.26 - 4.87 (m, 4H), 5.98 - 6.10 (m, 1H), 6.44 - 6.50 (m, 1H), 6.59 - 6.74 (m, 1H), 7.22 - 7.26 (m, 1H), 7.34 - 7.47 (m, 2H), 9.87 (d, J= 12 Hz, 1H), 10.19 - 10.21 (m, 1H).

[0309] LCMS (Method A): 1.085 min, MS: ES+ 443.9 (M+1).

[0310] Analytical HPLC (Method D): 4.78 min Prep HPLC purification method

[0311] Chromatographic separation and isolation were conducted with Shimazu NEXERA purification system with UV detector; column Shim-Pack GIST C18 (250 mm x 20 mm x 5µm); compounds were eluted with, Mobile Phase A : 0.05% TFA in water, Mobile Phase B : Acetonitrile with a gradient of T = 0 min (85% A, 15% B); gradient to T = 21.00 min (62% A, 38% B); T = 21.01 min (2% A, 98% B); gradient to T = 23.0 min (2% A, 98% B); T= 23.01 min (85% A, 15% B); gradient to T = 26.00 min (85% A, 15% B); Flow rate= 20 mL / min; analysis time 26 min.Example 1.1: (E)-N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)-4- (dimethylamino)but-2-enamide Step 1: (4-(Benzylamino)isoindolin-2-yl)(2,4-dihydroxyphenyl)methanone

[0312] The title compound was prepared from N-benzylisoindolin-4-amine hydrochloride (Intermediate E) and 2,4-dihydroxybenzoic acid (CAS 89-86-1) analogously to Example 1 Step 1.

[0313] 1H NMR (DMSO-d6, 400 MHz): δ 2.73 (s, 1H), 2.89 (s, 1H), 4.31 (d, J= 20 Hz, 2H), 4.70 (t, J= 12 Hz, 4H), 6.11 - 6.54 (m, 5H), 6.96 (d, J= 8 Hz, 1H), 7.20 - 7.35 (m, 5H), 9.72 (s, 1H, D2O exchangeable), 10.56 (d, J= 36 Hz, 1H, D2O exchangeable).

[0314] LCMS (Method A): 2.012 min, MS: ES+ 361 (M+1) Step 2: (E)-N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide

[0315] The title compound was prepared from (4-(benzylamino)isoindolin-2-yl)(2,4- dihydroxyphenyl)methanone (Step 1) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) analogously to Example 1 Step 2.

[0316] 1H NMR (DMSO-d6, 400 MHz): δ 1.99 (s, 6H), 2.86 (s, br, 2H), 4.07 - 4.32 (m, 1H), 4.44 - 4.57 (m, 1H), 4.79 (s, 3H), 5.01 (d, J= 12 Hz, 1H), 5.72 (t, J= 12 Hz, 1H), 6.27 - 6.32 (m, 2H), 6.71 – 6.91 (m, 3H), 6.98 (d, J= 8 Hz, 1H), 7.11 - 7.31 (m, 6H), 9.73 (s, 1H, D2O exchangeable), 10.34 (s, 1H, D2O exchangeable).

[0317] LCMS (Method A): 1.272 min, MS: ES+ 472.2 (M+1).

[0318] Analytical HPLC (Method B): 4.737 min,Example 1.2: (E)-N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)but-2-enamide Step 1: (4-(Benzylamino)isoindolin-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone

[0319] The title compound was prepared from N-benzylisoindolin-4-amine hydrochloride (Intermediate E) and 2,4-dihydroxy-5-methylbenzoic acid (Intermediate F) analogously to Example 1 Step 1.

[0320] 1H NMR (DMSO-d6, 400 MHz): δ 2.07 (s, 3H), 4.28 - 4.33 (m, 2H), 4.65 - 4.72 (m, 4H), 6.08 - 6.27 (m, 2H), 6.40 - 6.52 (m, 2H), 6.96 (s, 1H), 7.07 (s, 1H), 7.19 (s, 1H), 7.30 - 7.36 (m, 4H), 9.64 (d, J=8 Hz, 1H, D2O exchangeable), 10.12 - 10.22 (m, 1H, D2O exchangeable).

[0321] LCMS (Method A): 2.124 min, MS: ES+ 375.1 (M+1) Step 2: (E)-N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino) but-2-enamide

[0322] The title compound was prepared from (4-(benzylamino)isoindolin-2-yl)(2,4-dihydroxy- 5-methylphenyl)methanone (Step 1) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) analogously to Example 1 Step 2.

[0323] 1H NMR (DMSO-d6, 400 MHz): δ 2.01 (s, 6H), 2.08 (s, 3H), 2.89 (s, br, 2H), 4.06 (d, J= 16 Hz, 1H), 4.28 (d, J= 16 Hz, 1H), 4.43 - 4.56 (m, 1H), 4.78 (s, 4H), 5.01 (d, J= 16 Hz, 1H), 5.74 (d, J= 16 Hz, 1H), 6.38 (s, 1H), 6.60 - 6.79 (m, 2H), 6.90 (d, J= 8 Hz, 2H), 7.18 - 7.34 (m, 7H), 9.65 (s, 1H, D2O exchangeable), 9.89 and 10.06 (singlets, 1H, D2O exchangeable).

[0324] LCMS (Method A): 1.372 min, MS: ES+ 486.2 (M+1).

[0325] Analytical HPLC (Method B): 4.93 min.Example 1.3: (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(diethylamino)-N-((1- methyl-1H-pyrazol-4-yl)methyl)but-2-enamide Step 1: (2, 4-Dihydroxyphenyl) (4-(((1-methyl-1H-pyrazol-4-yl) methyl) amino) isoindolin-2-yl) methanone

[0326] The title compound was prepared from N-((1-methyl-1H-pyrazol-4-yl) methyl) isoindolin- 4-amine (Intermediate L) and 2,4-dihydroxybenzoic acid (CAS 89-86-1) analogously to Example 1 Step 1.

[0327] 1H NMR (DMSO-d6, 400 MHz): δ 3.75 (s, 3H), 4.02 - 4.13 (m, 2H), 4.61 - 4.72 (m, 4H), 5.69 (s, 1H D2O exchangeable), 6.29 - 6.33 (m, 2H), 6.46 - 6.57(m, 2H), 7.04 (d, J= 6.8 Hz, 1H), 7.24 (d, J= 8.8 Hz, 1H), 7.34 (d, J= 16.8 Hz, 1H), 7.55 (d, J= 16 Hz, 1H). 9.72 (s, 1H, D2O exchangeable), 10.5 and 10.6 (2 singlets, 1H, D2O exchangeable)

[0328] LCMS (Method A): 1.468 min, MS: ES+ 365 (M+1). Step 2: (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(diethylamino)-N-((1-methyl-1H- pyrazol-4-yl)methyl)but-2-enamide

[0329] The title compound was prepared from (2,4-dihydroxyphenyl) (4-(((1-methyl-1H-pyrazol- 4-yl) methyl) amino) isoindolin-2-yl) methanone (Step 1) and (E)-4-(dimethylamine) but-2-enoic acid hydrochloride (CAS: 848133-35-7) analogously to Example 1 Step 2.

[0330] 1H NMR (DMSO-d6, 400 MHz, D2O exchange) δ 2.06 (s, 6H), 2.95 (s, br, 2H), 3.69 - 3.82 (m, 3H), 4.35 - 4.83 (m, 6H), 5.67 – 5.77 (m, 1H), 6.28 - 6.33 (m, 2H), 6.70 (bs, 1H), 6.98 - 7.15 (m, 3H), 7.35 - 7.51 (m, 3H).

[0331] LCMS (Method A): 0.977 min, MS: ES+ 475.1 (M+1).

[0332] Analytical HPLC (Method D): 4.392 min. Prep. HPLC purification method.

[0333] Chromatographic separation and isolation were conducted with Shimadzu Nexera prep with Lh-40 auto purification system. The column used was Shim-Pack GIST C18 (250 mm x 20 mm x 5 µm) and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : Methanol with a gradient of T = 0.01 min (87% A, 13% B); gradient to T = 24.00 min (63% A, 37% B); T = 24.01 min (2% A, 98% B) gradient to T = 26.00 min (2% A, 98% B); T = 26.01 min (87% A, 13% B); gradient to T = 30 min (87% A, 13% B); Flow rate= 14 mL / min; analysis time 30 min. Example 2: (E)-4-(3,3-Difluoropyrrolidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl) isoindolin-4-yl)but-2-enamide Step 1: (E)-N-(2-(2,4-bis(Methoxymethoxy)-5-methylbenzoyl)isoindolin-4-yl)-4-(3,3- difluoropyrrolidin-1-yl)but-2-enamide

[0334] To a cooled (0 ˚C) solution of (E)-4-(3,3-difluoropyrrolidin-1-yl)but-2-enoic acid (Intermediate D) (0.35 g, 1.83 mmol, 1.0 eq.) in DCM (3.5 mL) were added CO2Cl2 (1.7 mL) and cat. DMF (2-3 drops) under nitrogen and the mixture was stirred at 0 ˚ C for 15 mins. The resulting mixture was concentrated under reduced pressure (under nitrogen), the intermediate was dissolved in THF (3.5 mL) and cooled to 0 ˚C. To this mixture was added a solution of (4- aminoisoindolin-2-yl)(2,4-bis(methoxymethoxy)-5-methylphenyl)methanone (Intermediate C) (0.2 g, 0.49 mmol, 0.3 eq.) and DIPEA (0.7 g, 5.49 mmol, 3.0 eq.) and the resulting mixture was allowed to stir at room temperature for 1 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by chromatography on silica (product eluted in 3.6% MeOH in DCM) to afford the title compound (0.16 g, Yield: 31%).

[0335] 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s, 3H), 2.20 - 2.34 (m, 2H), 2.67 - 2.78 (m, 2H), 2.86 - 2.98 (m, 2H), 3.24 - 3.25 (m, 1H), 3.28 - 3.31 (m, 4H), 3.42 (s, 3H), 4.59 (s, br, 2H), 4.80 (d, J= 14.8 Hz, 2H), 5.17 (s, 2H), 5.26 (s, 2H), 6.56 - 6.80 (m, 2H), 6.92 (d, J= 3.6 Hz, 1H), 7.04(d, J= 7.6 Hz, 1H), 7.13 - 7.17 (m, 2H), 7.26 - 7.30 (q, J= 7.6 Hz, 15.6 Hz, 1H), 7.67 (t, J= 7.6 Hz, 1H).

[0336] LCMS (Method A): 1.335 min, 1.420 min, 1.487 min, 1.518 min, MS: ES+ 546 (M+1). Step 2: (E)-4-(3,3-Difluoropyrrolidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4- yl)but-2-enamide

[0337] To a stirred solution of (E)-N-(2-(2,4-bis(methoxymethoxy)-5-methylbenzoyl)isoindolin- 4-yl)-4-(3,3-difluoropyrrolidin-1-yl)but-2-enamide (Step 1) (0.16 g, 0.29 mmol, 1.0 eq.) in EtOH (1.6 mL) was added dropwise 4M HCl in dioxane (0.8 mL) at 0 ˚C. The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure to afford the title compound (0.045 g, Yield: 34%).

[0338] 1H NMR (DMSO-d6, 400 MHz): δ 2.03 (s, 3H), 2.27 - 2.33 (m, 2H), 2.67 - 2.74 (m, 2H), 2.91 - 2.94 (m, 2H), 3.27 - 3.34 (m, 2H), 4.70 - 4.80 (m, 4H), 6.31 (s, 1H), 6.65 - 6.75 (m, 1H), 7.06 - 7.15 (m, 2H), 7.26 - 7.27 (m, 1H), 7.66 (d, J= 7.2 Hz, 1H), 9.63 - 9.72 (m, 2H, D2O exchangeable), 9.98 - 10.17 (m, 1H, D2O exchangeable).

[0339] LCMS (Method A): 1.208 min, MS: ES+ 458 (M+1).

[0340] Analytical HPLC (Method B): 4.638 min. Prep. HPLC purification method.

[0341] Chromatographic separation and isolation were conducted with a Waters 2545 purification system with UV detector. The column used was SUNFIRE, C18, OBD (19 x 250)mm, 5μm and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = 0 min (75% A, 25% B); gradient to T = 17.00 min (65% A, 35% B); T = 17.01 min (02% A, 98% B) gradient to T = 20.00 min (02% A, 98% B); T = 20.01 min (75% A, 25% B); gradient to T = 24 min (75% A, 25% B); Flow rate= 13 mL / min; analysis time 24 min. Example 2.1: ((E)-4-(3,3-Difluoroazetidin-1-yl)-N-(2-(2,4-dihydroxy-5- methylbenzoyl)isoindolin-4-yl)but-2-enamideStep 1: (E)-N-(2-(2,4-bis(Methoxymethoxy)-5-methylbenzoyl) isoindolin-4-yl)-4-(3,3- difluoroazetidin-1-yl) but-2-enamide

[0342] The title compound was prepared from (E)-4-(3,3-difluoroazetidin-1-yl) but-2-enoic acid (Intermediate DA) and (4-Aminoisoindolin-2-yl)(2,4-bis(methoxymethoxy)-5- methylphenyl)methanone (Intermediate C) analogously to Example 2 Step 1. The compound was used directly in Step 2. LCMS (Method A): 1.410 min, 1.437 min, 1.521 min, 1.546 min, MS: ES+ 535.1 (M+1). Step 2: ((E)-4-(3,3-Difluoroazetidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4- yl)but-2-enamide

[0343] The title compound was prepared from (E)-N-(2-(2,4-bis(methoxymethoxy)-5- methylbenzoyl) isoindolin-4-yl)-4-(3,3-difluoroazetidin-1-yl) but-2-enamide and 4M HCl in dioxane analogously to Example 2 Step 2.

[0344] High temperature1H NMR (DMSO-d6, 400 MHz, 348K): δ 2.07 (s, 3H), 3.40 (d, J= 4 Hz, 2H), 3.63-3.69 (t, J= 12 Hz, 4H), 4.83 (d, J= 12.8 Hz, 4H), 6.35 - 6.40 (m, 2H), 6.69 - 6.74 (m, 1H), 7.11 (d, J= 8.8 Hz, 2H), 7.29 - 7.25 (t, J= 8 Hz, 1H), 7.64 (d, J= 8 Hz, 1H), 9.43 (m, 2H, D2O exchangeable), 10.08 (s, 1H, D2O exchangeable).

[0345] LCMS (Method A): 1.208 min, MS: ES+ 444 (M+1).

[0346] Analytical HPLC (Method B): 4.514 min, Prep HPLC purification method.

[0347] Chromatographic separation and isolation were conducted with a Waters 2545 purification system with UV detector. The column used was SUNFIRE, C18, OBD 19 x 250 mm, 5μm and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : 20% A Line in Acetonitrile with a gradient of T = 0 min (78% A, 22% B); gradient to T = 15.00 min (68% A, 32% B); T = 15.01 min (2% A, 98% B); gradient to T = 18.0 min (2% A, 98%B); T= 18.01 min (78% A, 22% B); gradient to T = 24.00 min (78% A, 22% B); Flow rate= 19 mL / min; analysis time 24 min. Example 3: N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl) acrylamide Step 1: (2,4-Dihydroxy-5-methylphenyl)(4-nitroisoindolin-2-yl)methanone:

[0348] The title compound was prepared from 2,4-dihydroxy-5-methylbenzoic acid (Intermediate F) and 4-nitroisoindoline hydrochloride (Intermediate C Step 1c) analogously to Example 1 Step 1.

[0349] 1H NMR (DMSO-d6, 400 MHz): δ 2.04 (s, 3H), 4.90 (s, 2H), 5.19 (s, br, 2H), 6.43 (s, 1H), 7.06 (s, br, 1H), 7.62 (t, J= 8 Hz, 1H), 7.78 - 7.84 (m, 2H), 8.15 (d, J= 8.4 Hz, 1H), 9.68 (s, 1H, D2O exchangeable), 9.97 and 10.1 (singlets, br, 1H, D2O exchangeable).

[0350] LCMS (Method A): 1.606 min, MS: ES+ 315.1 (M+1). Step 2: (4-Aminoisoindolin-2-yl) (2, 4-dihydroxy-5-methylphenyl) methanone

[0351] To a stirred solution of (2,4-dihydroxy-5-methylphenyl) (4-nitroisoindolin-2- yl)methanone (Step 1) (1.0 g, 3.18 mmol, 1 eq.) in EtOH (10 mL) and water (5 mL) were added NH4Cl (2.53 g, 4.78 mmol, 15.0 eq.) and Fe powder (2.14 g, 38.21 mmol, 6.0 eq.) and the reaction mixture heated to 70 ˚C for 3 h. The resulting mixture was filtered through Celite® and the filter cake washed with 10% MeOH: DCM (4 x 100 mL). The filtrate was poured in water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum to afford the title compound as a brown solid (0.8 g, Yield: 94%).

[0352] 1H NMR (MeOD-d6, 400 MHz): δ 2.14 (s, 3H), 4.77 (s, br, 2H), 4.92 (s, br, 2H), 6.39 (s, br, 1H), 6.63 (s, br, 2H), 7.06 - 7.14 (m, 2H).

[0353] LCMS (Method A): 1.287 min, MS: ES+ 284.79 (M+1).Step 3: N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl) acrylamide

[0354] To a stirred solution of (4-aminoisoindolin-2-yl) (2, 4-dihydroxy-5-methylphenyl) methanone (Step 2) (0.200 g, 0.704 mmol, 1 eq.) in acetic acid (2 mL) was added dropwise acrylic anhydride (0.089 g, 0.704 mmol, 1 eq.) at 0 ˚C. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was poured into ice-cold water (100 mL), neutralized using saturated solution of K2CO3solution (pH ~10) and extracted in EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude material was purified by chromatography on silica (product eluted in 3.4% MeOH in DCM) to afford the title compound as an off-white solid (0.065 g, Yield: 27.3%).

[0355] High temperature1H NMR (DMSO-d6, 400 MHz): δ 2.07 (s, 3H), 4.82 - 4.86 (m, 4H), 5.73 - 5.76 (m, 1H), 6.25 - 6.29 (m, 1H), 6.41 (s, 1H), 6.50 - 6.57 (m, 1H), 7.12 (d, J= 6.8 Hz, 2H), 7.28 (t, J= 7.6 Hz, 1H), 7.62 (d, J= 8 Hz, 1H), 9.40 (s, 1H), 9.58 (s, 1H), 10.09 (s, 1H).

[0356] LCMS (Method A): 1.398 min, MS: ES+ 338.8 (M+1).

[0357] Analytical HPLC (Method B): 6.13 min. Example 4: (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- 4-(dimethylamino)but-2-enamide Step 1: tert-Butyl (E)-7-(4-(dimethylamino)but-2-enamido)-3,4-dihydroisoquinoline-2(1H)- carboxylate

[0358] To a stirred solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) (1 g, 6.02 mmol, 1 eq.) in DMF (15 mL) was added EDC.HCl (1.7 g, 9.03 mmol, 1.5 eq.) and HOAT (0.82 g, 6.02 mmol, 1 eq.) and the reaction mixture was stirred at room temperature for 30 mins. tert-Butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (Intermediate H) (1.5 g, 6.02 mmol, 1 eq.) and NMM (1.21 g, 12.04 mmol, 2 eq.) were added and stirring continued at room temperature for 2 h. The resulting mixture diluted with water (100 mL)and extracted with EtOAc (4 x 30 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude material was purified by chromatography on silica (product eluted at 3.5% MeOH in DCM) to afford the title compound as a brown solid (3.5 g, Yield: Quantitative)

[0359] 1H NMR (DMSO-d6, 400 MHz): δ 1.42 (s, 9H), 2.26 (s, 6H), 2.71 (t, J= 5.6 Hz, 2H), 2.17 (t, J= 6.0 Hz, 2H), 3.53 (t, J= 5.6 Hz, 2H), 4.45 (s, br, 2H), 6.28 (d, J= 15.2 Hz, 1H), 6.68 - 6.75 (m, 1H), 7.09 (d, J= 8.4 Hz, 1H), 7.34 - 7.38 (m, 1H), 7.50 (bs, 1H), 10.05 (s, 1H).

[0360] LCMS (Method A): 1.373 min, MS: ES+ 359.9 (M+1). Step 2: (E)-7-(4-(Dimethylamino)but-2-enamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0361] To a cooled (0 ˚C) solution of tert-butyl (E)-7-(4-(dimethylamino)but-2-enamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate (Step 1) (3.5 g, 9.74 mmol, 1 eq.) in DCM (35 mL) was added dropwise 4M HCl in dioxane (35 mL) and reaction mixture was stirred at 0 ˚C for 2 h. The resulting mixture was concentrated under vacuum and the crude material was triturated with diethyl ether (7 x 20 mL) and dried under vacuum to yield the title compound as a light yellow solid (3.0 g, Yield: quantitative).

[0362] 1H NMR (DMSO-d6, 400 MHz): δ 2.74 (d, J= 4.8 Hz, 6H), 2.95 (t, J= 5.6 Hz, 2H), 3.32 (bs, 2H), 3.91 (t, J= 5.6 Hz, 2H), 4.22 (bs, 2H), 6.54 (d, J= 15.6 Hz, 1H), 6.77 - 6.85 (m, 1H), 7.17 (d, J= 8.4 Hz, 1H), 7.50 - 7.55 (m, 1H), 7.61 (s, 1H), 9.57 (bs, 2H), 10.66 (s, 1H), 11.12 (bs, 1H). HCl salt.

[0363] LCMS (Method C): 4.186 min, MS: ES+ 260.2 (M+1). Step 3: (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)but-2-enamide

[0364] To a stirred solution of 2,4-dihydroxy-6-methylbenzoic acid (Intermediate G) (0.3 g, 1.78 mmol, 1 eq.) in DMF (15 mL) was added EDC.HCl (0.513 g, 2.67 mmol, 1.5 eq.) and HOAT(0.242 g, 1.78 mmol, 1 eq.) at room temperature and the mixture was stirred for 30 mins. (E)-4- (Dimethylamino)-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)but-2-enamide hydrochloride (Step 2) (0.632 g, 2.14 mmol, 1.2 eq.) and NMM (0.97 mL, 8.90 mmol, 5 eq.) were added and stirring continued at room temperature for 16 h. The resulting mixture was purified directly by reverse phase purification (product eluted at 50% acetonitrile in water). The material was further triturated with MeOH (3 x 5 mL) to afford the title compound as a grey solid (0.143 g, Yield: 20%)

[0365] High temperature1H NMR (DMSO-d6, 400 MHz, 349K): δ 1.99 (s, 3H), 2.21 (s, 6H), 2.68 - 2.78 (m, 4H), 3.53 - 3.55 (m, 2H), 4.55 - 4.58 (m, 2H), 6.13 - 6.26 (m, 3H), 6.71 - 6.75 (m, 1H), 7.08 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 7.2 Hz, 1H), 9.05 - 9.10 (m, 2H), 9.75 (bs, 1H).

[0366] LCMS (Method A): 0.996 min, MS: ES+ 410 (M+1).

[0367] Analytical HPLC (Method B): 4.357 min. Example 4.1: (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)-4-(dimethylamino)but-2-enamide

[0368] To a stirred solution of 2,4-dihydroxy-5-methylbenzoic acid (Intermediate F) (0.2 g, 1.19 mmol, 1 eq.) in DMF (5 mL) were added EDC.HCl (0.342 g, 1.78 mmol, 1.5 eq.) and HOAT (0.161 g, 1.18 mmol, 1 eq.) and the mixture was stirred at room temperature for 10 mins. (E)-4- (Dimethylamino)-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)but-2-enamide (Example 4 step 2) (0.422 g, 1.42 mmol, 1.2 eq.) and NMM (0.600 g, 5.94 mmol, 5 eq.) were added and stirring continued at room temperature for 1.5 h. The resulting mixture was poured in water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with cold brine solution (2 x 10 mL), dried over Na2SO4and concentrated under vacuum. The crude material was purified by Prep-HPLC followed by lyophilization of the product fractions to afford the title compound (0.160 g, Yield: 15.00%).

[0369] High temperature1H NMR (DMSO-d6, 400 MHz, 344K): δ 2.09 (s, 3H), 2.17 (s, 6H), 2.67 - 2.80 (m, 2H), 3.37 (d, J= 5.6 Hz, 2H), 3.63 - 3.66 (m, 2H), 4.60 (s, 2H), 6.23 - 6.26 (m, 1H), 6.40 (s ,1H), 6.70 - 6.77 (m, 1H), 6.80 (s, 1H), 7.08 - 7.10 (m, 1H), 7.39 - 7.45 (m, 2H), 9.30 - 9.33 (m, 2H), 9.77 (s, 1H). Formic salt.

[0370] LCMS (Method A): 1.095 min, MS: ES+ 409.9 (M+1).

[0371] Analytical HPLC (Method B): 4.581 min.Prep. HPLC purification method:

[0372] Chromatographic separation and isolation were conducted with flash chromatography- Selekt with uv detector; column YMC C18, 120gm, 50μm; compound eluted with, Mobile Phase A : 0.1% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = 0 min (100% A, 00% B); gradient to T = 25.00 min (80% A, 20% B); T = 25.01 min (00% A, 100% B) gradient to T = 30.00 min (00% A, 100% B); T = 30.01 min (100% A, 00% B); gradient to T = 35 min (100% A, 00% B); Flow rate= 70 mL / min; analysis time 35.01 min. Example 4.2: (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)-4-(dimethylamino)-N-methylbut-2-enamide Step 1: tert-Butyl (E)-7-(4-(dimethylamino)-N-methylbut-2-enamido)-3,4-dihydroisoquinoline- 2(1H)-carboxylate

[0373] Performed in 6 parallel batches, each of 0.5 g scale: To a stirred solution of (E)-4- (dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) (0.5 g, 3.01 mmol, 1.0 eq.) in DMF (0.5 mL) were added tert-butyl 7-(methylamino)-3,4-dihydroisoquinoline-2(1H)- carboxylate (Intermediate I) (0.395 g, 1.50 mmol, 0.5 eq.) and DCC (0.927 g, 4.5 mmol, 1.5 eq.) and the reaction mixture was heated to 150 ˚C using microwave irradiation for 15 mins. The resulting mixture was diluted with ice water (200 mL) and extracted with EtOAc (5 x 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by chromatography on silica (product eluted in 4.1% MeOH in DCM) to afford the title compound (2.4 g, Yield: 35%) which was used directly in Step 2. LCMS (Method A): 1.375 min, MS ES+: 374.2 (M+1). Step 2: (E)-4-(Dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)but-2-enamide hydrochloride

[0374] The title compound was prepared from tert-butyl (E)-7-(4-(dimethylamino)-N-methylbut- 2-enamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step 1) and 4M HCl in dioxane analogously to Example 4 Step 2 and used directly in Step 3.

[0375] LCMS (Method B): 1.55 min, MS: ES+ 273.38 (M+1). Step 3: (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide

[0376] The title compound was prepared from 2,4-dihydroxy-5-methylbenzoic acid (Intermediate F) and (E)-4-(dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)but- 2-enamide hydrochloride (Step 2) analogously to Example 4 Step 3.

[0377] 1H NMR (DMSO-d6, 400 MHz): δ 2.01 (s, 3H), 2.05 (s, 6H), 2.84 - 2.91 (m, 4H), 3.20 (s, 3H), 3.60 - 3.63 (m, 2H), 4.60 - 4.62 (m, 2H), 5.88 (d, J= 14.8 Hz, 1H), 6.38 (s, 1H), 6.57 - 6.64 (m, 1H), 6.85 (s, 1H), 7.05 - 7.10 (m, 2H), 7.22 (d, J= 8 Hz, 1H), 9.60 (bs, 2H).

[0378] LCMS (Method A): 1.123 min, MS: ES+ 424.11 (M+1).

[0379] Analytical HPLC (Method B): 4.279 min. Prep. HPLC purification method:

[0380] Chromatographic separation and isolation were conducted with a Waters 2545 purification system with UV detector. The column used was SUNFIRE, C18, OBD 19 x 250 mm, 5μm and the compounds were eluted with, Mobile Phase A : 0.05% FORMIC ACID IN WATER, Mobile Phase B : Acetonitrile with a gradient of T = 0 min (90% A, 10% B); gradient to T = 17.00 min (82% A, 18% B); T = 17.01 min (02% A, 98% B) gradient to T = 19.00 min (02% A, 98% B); T = 19.01 min (90% A, 10% B); gradient to T = 24 min (90% A, 10% B); Flow rate= 15 mL / min; analysis time 24.00 min. Example 4.3: (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)-4-(dimethylamino)-N-methylbut-2-enamide

[0381] The title compound was prepared from 2,4-dihydroxy-6-methylbenzoic acid (Intermediate G) and (E)-4-(dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)but- 2-enamide hydrochloride (Example 4.2 Step 2) analogously to Example 4 Step 3.

[0382] High temperature1H NMR (DMSO-d6, 400 MHz 348K): δ 2.00 (s, 3H), 2.07 (s, 6H), 2.86 - 2.90 (m, 4H), 3.22 (s, 2H), 3.53 (bs, 2H), 4.61 (bs, 2H), 5.91 (d, J= 15.4 Hz, 1H), 6.15 (d, J= 22.4 Hz, 2H), 6.57 - 6.64 (m, 1H), 7.04 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 1H), 9.04 (bs, 2H).

[0383] LCMS (Method A): 1.025 min, MS: ES+ 424.1 (M+1).

[0384] Analytical HPLC (Method B): 4.062 min Prep. HPLC purification method:

[0385] Chromatographic separation and isolation were conducted with a Waters 2545 purification system with UV detector. The column used was SUNFIRE, C18, OBD (19 x 250)mm, 5μm and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = 3 min (93% A, 7% B); gradient to T = 16.00 min (93% A, 7% B); T = 16.01 min (2% A, 98% B) gradient to T = 19.00 min (2% A, 98% B); T = 19.01 min (93% A, 7% B); gradient to T = 25 min (93% A, 7% B); Flow rate= 19 mL / min; analysis time 25 min. Example 4.4: (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)-4-(dimethylamino)-N-methylbut-2-enamide

[0386] The title compound was prepared from 2,4-dihydroxy-5-isopropylbenzoic acid (Intermediate FA) and (E)-4-(dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)but- 2-enamide hydrochloride (Example 4.2 Step 2) analogously to Example 4 Step 3.

[0387] 1H NMR (DMSO-d6, 400 MHz): δ 1.10 (d, J= 6.8 Hz, 6H), 2.06 (s, 6H), 2.85 - 2.91 (m, 4H), 3.05 - 3.08 (m, 1H), 3.20 (s, 3H), 3.37 – 3.63 (m, 2H), 4.64 (s, br, 2H), 5.85 (d, J= 13.6 Hz, 1H), 6.39 (s, 1H), 6.57 - 6.93 (m, 1H), 6.88 (s, 1H), 7.06 (d, J= 8 Hz, 1H), 7.12 (s, 1H), 7.23 (d, J= 8 Hz, 1H), 9.58 (s, 2H).

[0388] LCMS (Method A): 1.337 min, MS: ES+ 452.1 (M+1).

[0389] Analytical HPLC (Method D): 5.007 min. Example 5: (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(pyrrolidin-1- yl)but-2-enamide

[0390] The title compound was prepared from (E)-4-(pyrrolidin-1-yl) but-2-enoic acid hydrochloride (CAS: 848133-09-5) and (4-aminoisoindolin-2-yl) (2,4-dihydroxy-5- methylphenyl)methanone (Example 3, Step 2) analogously to Example 1 Step 2.

[0391] 1H NMR (DMSO-d6, 400 MHz): δ 1.71 (s, 4H), 2.00 (s, 3H), 2.50 - 2.67 (m, 4H), 3.23 (d, J= 5.2 Hz, 2H), 4.81 - 4.85 (m, 4H), 6.20 - 6.22 (s, br, 1H), 6.39 (d, J= 12 Hz, 1H), 6.75 - 6.81 (m, 1H), 7.07 - 7.11 (m, 2H), 7.26 (t, J= 8 Hz, 1H), 7.68 (d, J= 8 Hz, 1H), 9.65 (s, 1H), 10.33 (bs, 2H).

[0392] LCMS (Method I): 1.488 min, MS: ES+ 422.2 (M+1).

[0393] Analytical HPLC (Method C): 5.02 min. Prep. HPLC purification method:

[0394] Chromatographic separation and isolation were conducted with a Shimadzu Nexera purification system with UV detector. The column used was SHIMPACK GIST C18, (250 x 20)mm, 5μm and the compounds were eluted with, Mobile Phase A : 0.1% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = 0 min (80% A, 20% B); gradient to T = 18 min (78% A, 22% B); T = 18.01 min (02% A, 98% B); gradient to T = 20.00 min (02% A, 98% B); T = 20.01 min (80% A, 20% B) to T=22 min (80% A, 20% B); Flow rate= 20 mL / min; analysis time 22 min.Example 5.1: (E)-N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl)-4-morpholinobut- 2-enamide

[0395] The title compound was prepared from (E)-4 -morpholino-but-2-enoic acid hydrochloride (CAS: 1419865-05-6) and (4-aminoisoindolin-2-yl) (2, 4-dihydroxy-5-methylphenyl) methanone (Example 3 Step 2) analogously to Example 1 Step 2.

[0396] High Temperature1H NMR (DMSO-d6, 400 MHz): δ 2.07 (s, 3H), 2.40 - 2.43 (m, 4H), 3.61 - 3.63 (m, 4H), 3.62 (m, 4H), 4.82 - 4.85 (m, 4H), 6.36 - 6.40 (m, 2H), 6.74 - 6.78 (m, 1H), 7.10 - 7.12 (m, 2H), 7.27 (t, J= 7.6 Hz, 1H), 7.62 (d, J= 4.6 Hz, 1H), 9.42 (bs, 1H), 9.49 (bs, 1H), 10.09 (bs, 1H).

[0397] LCMS (Method A): 1.103 min, MS: ES+ 438.0 (M+1).

[0398] Analytical HPLC (Method B): 4.38 min. Example 6: N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin- 7-yl)-N-methylacrylamide Step 1: (3-Chloro-4,6-dihydroxy-2-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinolin-2(1H)- yl)methanone

[0399] To a stirred solution of 3-chloro-4,6-dihydroxy-2-methylbenzoic acid (Intermediate B) (0.7 g, 3.45 mmol, 1 eq.) in DMF (7 mL) were added EDC.HCl (0.995 g, 5.18 mmol, 1.5 eq) and HOAT (0.469 g, 3.45 mmol, 1 eq) at 0 ˚C. The mixture was allowed to warm to room temperature and treated with N-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate J) (0.8 g, 4.14 mmol, 1.2 eq.) and NMM (1.74 g, 17.27 mmol, 5 eq.). The reaction mixture was stirred at room temperature for 30 mins. The resulting mixture was poured into ice cold water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried overNa2SO4and concentrated under reduced pressure. The crude material was purified by chromatography on silica (product eluting at 4% MeOH: DCM) to afford the title compound as an off-white solid (0.18 g, Yield: 15%).

[0400] 1H NMR (DMSO-d6, 400 MHz): δ 2.00 - 2.08 (2 singlets, 3H), 2.57 - 2.69 (m, 5H), 3.35 (s, 1H), 3.59 - 3.96 (m, 1H), 4.17 - 4.29 (m, 1H), 4.60 – 4.70 (m, 1H), 5.49 (s, br, 1H, D2O exchangeable), 6.11 - 6.45 (m, 3H), 6.82 - 6.88 (m, 1H), 9.65 (d, J= 12 Hz, 1H, D2O exchangeable), 10.08 (d, J= 2 Hz, 1H, D2O exchangeable).

[0401] LCMS (Method A): 1.061 min, MS: ES+ 346.9 (M+1)

[0402] Analytical HPLC (Method D): 3.727 min, Step 2: N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide

[0403] Performed in 2 parallel batches, each of 0.12 g scale: To a cooled (0 ˚C) stirred solution of (3-chloro-4,6-dihydroxy-2-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinolin-2(1H)- yl)methanone (Step 1) (0.12 g, 0.34 mmol, 1.0 eq.) in DCM (1.2 mL) were added pyridine (0.26 g, 0.3.46 mmol, 10.0 eq.) and acrylic anhydride (0.065 g, 0.52 mmol, 1.5 eq.) and the mixture was stirred at 0 ˚C for 2 h. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over Na2SO4 and reduced under vacuum. The crude material was purified by chromatography on silica (product eluted at 3.7% MeOH in DCM) to afford the title compound as white solid (0.023 g, Yield: 8.3 %).

[0404] 1H NMR (DMSO-d6, 400 MHz): δ 1.99 and 2.10 (2 singlets, 3H), 2.71 - 2.74 (m, 1H), 2.80 - 2.86 (m, 1H), 3.17 - 3.24 (2 singlets, 3H), 3.38 - 3.43 (m, 1H), 3.68 - 4.02 (m, 1H), 4.31 - 4.42 (m, 1H), 4.72 - 4.85 (m, 1H), 5.59 (t, J= 12.8 Hz, 1H), 6.04 - 6.18 (m, 2H), 6.45 (d, J= 8 Hz, 1H), 7.04 - 7.09 (m, 1H), 7.18 - 7.26 (m, 2H), 9.65 - 9.71 (m, 1H, D2O exchangeable), 10.11 (d, J= 4 Hz, 1H, D2O exchangeable).

[0405] LCMS (Method A): 1.459 min, MS ES+: 401 (M+1).

[0406] Analytical HPLC (Method D): 5.471 min,Example 6.1: N-(2-(5-Chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide Step 1: (5-Chloro-2,4-dihydroxyphenyl)(7-(methylamino)-3,4-dihydroisoquinolin-2(1H)- yl)methanone

[0407] The title compound was prepared from 5-chloro-2,4-dihydroxybenzoic acid (Intermediate Q) and N-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate J) analogously to Example 6 Step 1. This material was progressed directly to Step 2.

[0408] LCMS (Method A): 1.016 min, MS: ES+ 332.9 & 334.6 (M+1 & M+3). Step 2: N-(2-(5-Chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide

[0409] The title compound was prepared from (5-chloro-2,4-dihydroxyphenyl)(7- (methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Step 1), acetic acid and acrylic anhydride analogously to Example 3, Step 3.

[0410] 1H NMR (DMSO-d6, 400 MHz, D2O exchange): δ 2.83 (t, J= 5.2 Hz, 2H), 3.21 (s, 3H), 3.58 (bs, 2H), 4.65 (bs, 2H), 5.56 (d, J= 11.6 Hz, 1H), 6.09 - 6.16 (m, 2H), 6.57 (s, 1H), 7.06 - 7.09 (m, 2H), 7.15 (bs, 1H), 7.24 (d, J= 8.0 Hz, 1H).

[0411] LCMS (Method A): 1.423 min, MS: ES+ 387 & 389 (M+1 & M+3).

[0412] Analytical HPLC (Method D): 5.538 min. Prep. HPLC purification method:

[0413] Chromatographic separation and isolation were conducted with Shimadzu Nexera prep with LH-40 auto purification system. The column used was Shim-Pack GIST C18 (250 mm x 20mm x 5 µm) and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = 0.01 min (90% A, 10% B); gradient to T = 17.00 min (47% A, 53% B); T = 17.01 min (2% A, 98% B) gradient to T = 19.00 min (2% A, 98% B); T = 19.01 min (90% A, 10% B); gradient to T = 22 min (90% A, 10% B); Flow rate= 22 mL / min; analysis time 22 min. Example 7.1: (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide Step 1: (5-(tert-Butyl)-2-hydroxy-4-methoxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone

[0414] To a stirred solution of 5-(tert-butyl)-2-hydroxy-4-methoxybenzoic acid (Intermediate N) (0.73 g, 3.25 mmol, 1.0 eq.) in DMF (15 mL) were added EDC.HCl (0.93 g, 4.88 mmol, 1.5 eq.) and HOAT (0.44 g, 3.25 mmol, 1.0 eq.) and the reaction mixture was stirred at room temperature for 30 mins. N-Methylisoindolin-4-amine hydrochloride (Intermediate A) (0.57 g, 3.90 mmol, 1.2 eq.) and NMM (1.64 g, 16.2 mmol, 5.0 eq.) were added and stirring continued for 3 h. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. Purification of the crude material by chromatography on silica (product eluted at 3.4% MeOH: DCM) afforded the title compound as a light brown solid (0.6 g, Yield: 18.1%).

[0415] 1H NMR (DMSO-d6, 400 MHz): δ 1.30 (s, 9H), 2.64 – 2.72 (m, 3H), 3.80 (s, 3H), 4.52 – 4.72 (m, 4H), 6.37 (d, J= 6.8 Hz, 1H), 6.52 (t, J= 17.6 Hz, 11.2 Hz, 2H), 7.10 (d, J= 7.6 Hz, 2H), 10.07 – 10.28 (m, 1H).

[0416] LCMS (Method A): 2.463 min. MS: ES+ 355.1 (M+1).

[0417] Analytical HPLC (Method B): 9.85 min. Step 2: (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)- N-methylbut-2-enamide

[0418] To a stirred solution (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) (0.08 g, 0.48 mmol, 1.0 eq.) in DMF (1.6 mL, 20v) were added DCC (0.198 g, 0.96 mmol, 2.0 eq.) and (5-(tert-butyl)-2-hydroxy-4-methoxyphenyl)(4-(methylamino)isoindolin-2- yl)methanone (Step 1) (0.07 g, 0.19 mmol, 0.4 eq.) and the reaction mixture was heated to 150 ˚C using microwave irradiation for 15 mins. The resulting mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. Purification of the crude material by Prep. HPLC (0.05% Formic acid in water:ACN) afforded the title compound as a light brown solid (0.005 g, Yield: 2%).

[0419] 1H NMR (DMSO-d6, 400 MHz): δ 1.29 (s, 9H), 2.01 (s, 6H), 2.87 (d, J= 4.8 Hz, 2H), 3.1 - 3.20 (m, 3H), 3.80 (s, 3H), 4.59 (d, J= 15.2 Hz, 1H), 4.71 - 4.89 (m, 3H), 5.75 (d, J= 14 Hz, 1H), 6.49 - 6.66 (m, 2H), 7.07 (s, 1H), 7.22 (d, J= 6.8 Hz, 1H), 7.36 - 7.44 (m, 2H), 10.32 (bs, 1H).

[0420] LCMS (Method A): 1.529 min. MS: ES+ 466.1 (M+1).

[0421] Analytical HPLC (Method D): 5.84 min. Prep. HPLC purification method.

[0422] Chromatographic separation and isolation were conducted with an FC-01 flash purification system (Buchi model C810); column YMC-120GM C18, 50µm; compound eluted with: Mobile Phase A : 0.1% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = Initial (100% A, 0% B); gradient to T = 5.00 min (100% A, 0% B); T = 30.00 min (70% A, 30% B) gradient to T = 30.01 min (0% A, 100% B); T = 35.00 min (0% A, 100% B); T = 35.01 min (100% A, 0% B); T = 40.00 min (100% A, 0% B); Flow rate= 70 mL / min; analysis time 40 min. Example 7.2: (E)-N-(2-(5-(tert-Butyl)-4-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide Step 1: (5-(tert-butyl)-4-fluoro-2-hydroxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone

[0423] The title compound was prepared from 5-(tert-butyl)-4-fluoro-2-hydroxybenzoic acid (Intermediate OA) and N-methylisoindolin-4-amine hydrochloride (Intermediate A) analogously to Example 7.1, Step 1.

[0424] 1H NMR (DMSO-d6, 400 MHz): δ 1.23 - 1.40 (m, 9H), 2.63 and 2.72 (singlets, 3H), 4.42 - 4.72 (m, 4H), 5.37 - 5.52 (m, 1H, D2O exchangeable), 6.37 (d, J= 10 Hz, 1H), 6.46 - 6.58 (m, 1H), 6.63 - 6.68 (dd, J= 4.4 Hz, 4.8 Hz, 1H), 7.06 - 7.15 (m, 2H), 10.29 (d, J= 17.6, 1H, D2O exchangeable ).

[0425] LCMS (Method A): 2.242 min, MS: ES+ 343.1 (M+1).

[0426] Analytical HPLC (Method D): 8.260 min, Step 2: (E)-N-(2-(5-(tert-Butyl)-4-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide

[0427] The title compound was prepared from (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) and (5-(tert-butyl)-4-fluoro-2-hydroxyphenyl)(4- (methylamino)isoindolin-2-yl)methanone (Step 1) analogously to Example 7.1, Step 2.

[0428] 1H NMR (DMSO-d6, 400 MHz): δ 1.29 (d, J= 4.8 Hz, 9H), 2.04 (s, 6H), 2.91 (d, J= 4.4, 2H), 3.20 and 3.24 (singlets, 3H), 4.48 - 4.88 (m, 4H), 5.75 (t, J= 14.8 Hz, 1H), 6.57 - 6.69 (m, 2H), 7.12 (d, J= 9.6 Hz, 1H), 7.22 (d, J= 7.6 Hz, 1H), 7.34 - 7.44 (m, 2H), 10.42 (s, 1H, D2O exchangeable).

[0429] LCMS (Method A): 1.476 min, MS: ES+ 454.3 (M+1).

[0430] Analytical HPLC (Method D): 4.760 min. Example 8: (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)-4-(dimethylamino)-N-methylbut-2-enamideStep 1: (4,6-Dihydroxy-2,3-dimethylphenyl)(7-(methylamino)-3,4-dihydroisoquinolin-2(1H)- yl)methanone

[0431] To a stirred solution of 4,6-dihydroxy-2,3-dimethylbenzoic acid (Intermediate K) (0.180 g, 0.989 mmol, 1.0 eq.) in DMF (0.9 mL) were added EDC.HCl (0.284 g, 1.483 mmol, 1.5 eq.) and HOAT (0.134 g, 0.989 mmol, 1.0 eq.) and the mixture was stirred at room temperature for 30 mins. N-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate J) (0.195 g, 0.989 mmol, 1.0 eq.) in DMF (0.9 mL) was added followed by NMM (0.49 g, 4.94 mmol, 5.0 eq.) were added and the reaction mixture was stirred at room temperature for 30 mins. The resulting mixture was diluted with ice cold water (100 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by chromatography on silica (product eluted at 70% EtOAc in hexane) to afford the title compound (0.120 g, Yield:37%) which was used directly in Step 2

[0432] LCMS (Method A): 0.998 min, MS: ES+327 (M+1). Step 2: (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide

[0433] To a stirred solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS:848133-35-7) (0.122g, 0.734 mmol, 1.0 eq.) and (4,6-dihydroxy-2,3-dimethylphenyl)(7- (methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (step 1) (0.120, 0.367mmol, 0.5 eq ) in DMF (1.2 mL) was added DCC (0.227 g, 1.102 mmol, 1.5 eq.) and the reaction mixture was heated to 150 ˚C using microwave irradiation for 15 mins. The resulting mixture was diluted with water (100 mL), acidified with dilute HCl and further extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by Prep-HPLC eluting with 0.05% formic acid in water / ACN to afford the title compound as a brown solid (0.005 g, Yield: 4.00%).

[0434] High temperature1H NMR (DMSO-d6, 400 MHz, 348.7K): δ 1.97 (s, 6H), 2.05 (s, 3H), 2.07 (s, 3H), 2.85 - 2.90 (m, 4H), 4.07 (bs, 1H), 4.39 (bs, 1H), 4.72 (bs, 2H), 5.91 (d, J= 15.6 Hz,1H), 6.29 (s, 1H), 6.59 - 6.62 (m, 1H), 7.02 - 7.23 (m, 3H), 8.20 (s, 1H, D2O exchangeable), 8.90 (s, br, D2O exchangeable).

[0435] LCMS (Method D): 1.431 min, MS: ES+ 438.4 (M+1).

[0436] Analytical HPLC (Method D): 3.839 min. Prep. HPLC purification method

[0437] Chromatographic separation and isolation were conducted with Shimadzu LC20AP with uv detector. The column used was Shim-Pack GIST C18 (250 mm x 20 mm x 5 µm) and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : Acetonitrile with a gradient of T = 0.01 min (88% A, 12% B); gradient to T = 18.00 min (75% A, 25% B); T = 18.01 min (2% A, 98% B) gradient to T = 20.00 min (2% A, 98% B); T = 20.01 min (88% A, 12% B); gradient to T = 23 min (88% A, 12% B); Flow rate= 22 mL / min; analysis time 23 min. Example 9: N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide Step 1: (2,4-Dihydroxy-5-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinolin-2(1H)- yl)methanone

[0438] To a stirred solution of 2,4-dihydroxy-5-methylbenzoic acid (Intermediate F) (0.5 g, 2.97 mmol, 1 eq.) in DCM: THF (10 mL) were added EDC.HCl (0.86 g, 4.46 mmol, 1.5 eq) and HOAT (0.4 g, 2.97 mmol, 1 eq) at room temperature. N-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine hydrochloride (Intermediate J) (0.58 g, 3.57 mmol, 1.2 eq) and NMM (1.5 g, 14.88 mmol, 2 eq.) were added and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (eluting product at 4% water: ACN) to afford the title compound as an off-white solid (0.4 g, Yield: 41.5%).

[0439] LCMS (Method A): 1.025 min, MS: ES+ 312.9 (M+1). This material was used directly in Step 2. Step 2: N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide

[0440] To a cooled (0 ˚C) solution of (2,4-dihydroxy-5-methylphenyl)(7-(methylamino)-3,4- dihydroisoquinolin-2(1H)-yl)methanone (0.27 g, 0.86 mmol, 1 eq.) (Step 1) in pyridine (2.7 mL) was added dropwise acrylic anhydride (0.12 mL, 0.951 mmol, 1.1 eq.) and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was neutralized with saturated citric acid solution (80 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were dried over Na2SO4and concentrated under reduced pressure. The crude material was purified using Prep. HPLC (0.05% formic acid n water: ACN, MeOH, IPA) to afford the title compound as an off-white solid (0.035 g, Yield: 11.6%).

[0441] 1H NMR (DMSO-d6, 400 MHz): δ 2.00 (s, 3H), 2.83 (t, J= 5.2 Hz, 2H), 3.21 (s, 3H), 3.62 (s, br, 2H), 4.64 (s, 2H), 5.56 (d, J= 11.6. Hz, 1H), 6.06 - 6.16 (m, 2H), 6.39 (s, 1H), 6.85 (s, 1H), 7.07 (t, J= 8.8 Hz, 7.65 Hz, 1H), 7.14 (s, 1H), 7.23 (d, J= 8 Hz, 1H), 9.55 (d, J= 7.2 Hz, 2H, D2O exchangeable).

[0442] LCMS (Method A): 1.461 min, MS: ES+ 367 (M+1).

[0443] Analytical HPLC (Method D): 6.203 min. Example 10: N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)acrylamide

[0444] The title compound was prepared from (4-(benzylamino)isoindolin-2-yl)(2,4- dihydroxyphenyl)methanone (Example 1.1 Step 1), acetic acid and acrylic anhydride analogously to Example 3, Step 3.

[0445] 1H NMR (DMSO-d6, 400 MHz): δ 4.32 - 4.51 (m, 2H), 4.85 (s, 3H), 4.92 - 4.94 (m, 1H), 5.61 (d, J= 10.4 Hz, 1H), 6.20 - 6.34 (m, 3H), 6.98 (t, J= 4.0 Hz, 1H), 7.15 - 7.24 (m, 6H), 7.34 (d, J= 4.8 Hz, 2H), 9.55 (s, 1H), 10.32 (s, 1H).

[0446] LCMS (Method A): 1.729 min, MS: ES+ 415.1 (M+1).

[0447] Analytical HPLC (Method D): 7.278 min. Prep. HPLC purification method:

[0448] Chromatographic separation and isolation were conducted with a Waters 2545 purification system with UV detector. The column used was Xtimate C18 (250 mm x 21.2 mm x 5 µm) and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : Acetonitrile: MeOH: IPA (65:25:10) with a gradient of T = Initial (55% A, 45% B); gradient to T = 17.00 min (55% A, 45% B); T = 17.01 min (2% A, 98% B) gradient to T = 19.00 min (2% A, 98% B); T = 19.01 min (55% A, 45% B); gradient to T = 23 min (55% A, 45% B); gradient to T = 23 min (55% A, 45% B); Flow rate= 22 mL / min; analysis time 23 min. Example 10.1: N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)acrylamide

[0449] The title compound was prepared from (4-(benzylamino)isoindolin-2-yl)(2,4-dihydroxy- 5-methylphenyl)methanone (Example 1.2 step 1), acetic acid and acrylic anhydride analogously to Example 3, Step 3.

[0450] 1H NMR (DMSO-d6, 400 MHz): δ 2.07 (s, 3H), 4.29 - 4.54 (m, 2H), 4.84 (bs, 4H), 5.61 (d, J= 9.2 Hz, 1H), 5.95 - 6.01 (m, 1H), 6.25 (dd, J= 2.0, 8.4 Hz, 1H), 6.39 (s, 1H), 6.97 - 6.99 (m, 2H), 7.17 - 7.25 (m, 5H), 7.30 - 7.34 (m, 2H), 9.45 (bs, 1H, D2O exchangeable), 9.97 (bs, 1H, D2O exchangeable).

[0451] LCMS (Method A): 1.829 min, MS: ES+ 429.0 (M+1).

[0452] HPLC (Method D): 7.57 min. Prep. HPLC purification method:

[0453] Chromatographic separation and isolation were conducted with a Waters 2545 purification system with a UV detector. The column used was Xtimate C18 (250 mm x 21.2 mm x 5 µm) and the compounds were eluted with, Mobile Phase A : 0.05% Formic acid in water, Mobile Phase B : 20% a line in acetonitrile + 10%THF with a gradient of T = Initial (52% A, 48% B); gradient to T = 24.00 min (52% A, 48% B); T = 24.01 min (2% A, 98% B) gradient to T = 26.00 min (2% A, 98% B); T = 26.01 min (52% A, 48% B); T = 28 min (52% A, 48% B); T = 28.01 min (52% A, 48% B); Flow rate= 20 mL / min; analysis time 28.01 min. Example 11: (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N- phenethylbut-2-enamide Step 1: (2,4-Dihydroxyphenyl) (4-(phenethyl amino) isoindolin-2-yl) methanone

[0454] To a cooled (0 ˚C) solution of 2,4-dihydroxybenzoic acid (CAS 89-86-1) (0.38 g, 1.62 mmol, 1 eq.) in DMF (4.0 mL) were added HATU (0.92 g, 2.43 mmol, 1.5 eq) and DIPEA (0.45 mL, 3.24 mmol, 2.0 eq.) and the mixture was stirred stir at 0˚C for 10 mins. N-Phenethylisoindolin- 4-amine hydrochloride (Intermediate M) (0.25 g, 1.62 mmol, 1 eq.) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude material was purified by chromatography on silica (product eluted at 2.0% MeOH in DCM) to afford the title compound (0.3 g, Yield: 47.6%).

[0455] 1H NMR (DMSO-d6, 400 MHz): δ 2.81 - 2.89 (m, 2H), 4.59 (d, J= 10 Hz, 2H), 4.72 (s, 2H), 5.48 (d, J = 24.8 Hz, 1H), 6.29 - 6.34 (m, 2H), 6.50 - 5.59 (m, 2H), 7.09 (d, J= 6.8 Hz, 1H), 7.21 - 7.29 (m, 6H), 9.71 (s, 1H, D2O exchangeable), 10.53 (s, 1H, D2O exchangeable).2 protons obscured under water peak.

[0456] LCMS (Method A): 2.116 min, MS: ES+ 375.1 (M+1). Step 2: (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-phenethylbut-2- enamide

[0457] The title compound was prepared from (E)-4-(dimethylamine) but-2-enoic acid hydrochloride (CAS: 848133-35-7 and (2, 4-dihydroxyphenyl) (4-(phenethylamine) isoindolin-2- yl) methanone (Step 1) analogously to Example 1 step 2.

[0458] 1H NMR (DMSO-d6, 400 MHz): δ 2.0 (s, 6H), 2.67 - 2.87 (m, 4H), 3.70 - 3.71 (m, 1H), 3.93 - 4.02 (m, 1H), 4.71 - 4.88 (m, 2H), 4.53 - 4.67 (m, 2H), 5.66 - 5.74 (m, 1H), 6.28 - 6.34 (m, 2H), 6.65 - 6.73 (m, 1H), 7.08 - 7.36 (m, 7H), 7.38 - 7.43 (m, 2H), 9.73 (s, 1H, D2O exchangeable), 10.37 (s, 1H, D2O exchangeable).

[0459] LCMS (Method A): 1.409 min, MS: ES+ 486.1 (M+1).

[0460] Analytical HPLC (Method D): 5.03 min. Example 11.1: (E)-N-(2-(2-Chloro-4,6-dihydroxybenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide Step 1: (2-Chloro-4,6-bis(methoxymethoxy)phenyl)(4-(methylamino)isoindolin-2-yl)methanone

[0461] The title compound was prepared from 2-chloro-4,6-bis(methoxymethoxy)benzoic acid (Intermediate P) and N-methylisoindolin-4-amine hydrochloride (Intermediate A) analogously to Example 1, Step 1. Material was used directly in Step 2

[0462] LCMS (Method A): 1.929 min.2.010 min, MS: ES+ 407.0 (M+1). Step 2: (2-Chloro-4,6-dihydroxyphenyl)(4-(methylamino)isoindolin-2-yl)

[0463] The title compound was prepared from (2-chloro-4,6-bis(methoxymethoxy)phenyl)(4- (methylamino)isoindolin-2-yl)methanone (step 1) and 4M HCl in dioxane analogously to Example 4, Step 2.

[0464] 1H NMR (DMSO-d6, 400 MHz): δ 2.62 and 2.72 (2 doublets, J= 4.8 Hz, 3H), 4.23 - 4.46 (m, 2H), 4.55 (s, 1H), 4.68 (s, 1H), 5.37 - 5.52 (m, 1H, D2O exchangeable), 6.34 - 6.40 (m, 3H), 6.46 - 6.57 (m, 1H), 7.07 - 7.14 (m, 1H), 9.97 (s, 2H, D2O exchangeable).

[0465] LCMS (Method A): 1.469 min. MS: ES+ 318.9 (M+1).

[0466] Analytical HPLC (Method D): 5.105 min. Step 3: (E)-N-(2-(2-Chloro-4,6-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide

[0467] The title compound was prepared from (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (CAS: 848133-35-7) and (2-chloro-4,6-dihydroxyphenyl)(4- (methylamino)isoindolin-2-yl)methanone (Step 2) analogously to Example 1, Step 2.

[0468] High temperature1H NMR (D2O Exchange, DMSO-d6, 400 MHz, 349K): 2.09 (s, 6H), 3.09 (s, 2H), 3.22 and 3.45 (2 singlets, 3H), 4.31 - 4.63 (m, 3H), 4.83 (s, 1H), 5.80 (s, 1H), 6.31 - 6.39 (m, 2H), 6.55 - 6.70 (m, 1H), 7.17 - 7.44 (m, 3H).

[0469] LCMS (Method A): 1.045 min. MS: ES+ 430.0 (M+1).

[0470] Analytical HPLC (Method D): 3.73 min. Example 12: (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3,3-dimethylindoline-5- carbonyl)isoindolin-4-yl)-N-methylbut-2-enamide

[0471] To a solution 6-hydroxy-3,3-dimethylindoline-5-carboxylic acid (Intermediate R) (0.07 g, 0.33 mmol, 1 eq.) in DMF (0.7 mL) were added EDC.HCl (0.096 g, 0.50 mmol, 1.5 eq.) and HOAT(0.045 g, 0.33 mmol, 1 eq.) and the mixture was stirred at room temperature for 15 mins. (E)-4- (Dimethylamino)-N-(isoindolin-4-yl)-N-methylbut-2-enamide hydrochloride (Intermediate S) (0.15 g, 0.50 mmol, 1.5 eq.) and NMM (0.17 g, 1.69 mmol, 5 eq.) were added and stirring continued at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) causing a solid to precipitate. The solid was collected by filtration, washed with water (3 x 5 mL) and purified by preparative HPLC eluting with 0.05% HCl in water / acetonitrile. The product fractions were lyophilized to afford the title compound. (0.012 g, Yield: 6%).

[0472] 1H NMR (DMSO-d6, 400 MHz, D2O exchange): 1.28 (s, 6H), 2.62 (s, 6H), 3.20 (bs, 3H), 3.55 (bs, 2H), 3.74 - 3.93 (m, 2H), 4.60 - 4.64 (m, 1H), 4.80 - 4.87 (m, 3H), 6.04 (d, J= 15.2 Hz, 1H), 6.53 (bs, 1H), 6.71 (s, 1H), 7.18 (bs, 1H), 7.20 - 7.26 (m, 1H), 7.43 - 7.44 (m, 2H).

[0473] LCMS (Method A): 1.100 min, MS: ES+ 449.1 (M+1).

[0474] Analytical HPLC (Method-D): 3.580 min. Prep. HPLC purification method:

[0475] Chromatographic separation and isolation were conducted with Shimadzu LC20AP with uv detector. The column used was Shim-Pack GIST C18 (250 mm x 20 mm x 5 µm) and the compounds were eluted with, Mobile Phase A : 0.05%HCL IN WATER, Mobile Phase B : Acetonitrile with a gradient of T = 0.01 min (90% A, 10% B); gradient to T = 17.00 min (74% A, 26% B); T = 17.01 min (2% A, 98% B) gradient to T = 19.00 min (2% A, 98% B); T = 19.01 min (90% A, 10% B); gradient to T = 23 min (90% A, 10% B); Flow rate= 20 mL / min; analysis time 23 min. Example 13.1: (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide

[0476] To a stirred solution of 4,6-dihydroxy-2,3-dimethyl-benzoic acid (Intermediate K) (150 mg, 0.41 mmol, 1.00 eq), HOBT (95 mg, 0.62 mmol, 1.5 eq), EDC (118 mg, 0.62 mmol, 1.5 eq) and (E)-4-(dimethylamino)-N-(isoindolin-4-yl)-N-methylbut-2-enamide dihydrochloride(Intermediate V1-1) (178 mg, 0.54 mmol, 1.3 eq) in DMF (4.6 mL) was added DIPEA (0.29 mL, 1.65 mmol, 4.00 eq). The reaction mixture was stirred at room temperature for 48 h. MP carbonate resin (3.0 eq) was added and the mixture was agitated for 1 hour using a shaker. The resulting mixture was filtered through a hydrophobic frit and concentrated under reduced pressure. Purification of the crude material by preparative HPLC (Method Prep-LC-2) afforded the title compound as a formate salt (12 mg, 6.4%).

[0477] ¹H NMR (400 MHz, DMSO) δ 1.93 - 2.03 (m, 12H), 2.77 - 2.89 (m, 2H), 3.08 - 3.23 (m, 3H), 4.59 - 4.88 (m, 2H), 5.66 - 5.80 (m, 1H), 6.30 - 6.32 (m, 1H), 6.60 - 6.73 (m, 1H), 7.19 - 7.23 (m, 1H), 7.28 - 7.33 (m, 2H), 7.37 - 7.46 (m, 2H), 8.21 (s, 1H).

[0478] LCMS (LC-Method 1): 2.66 min, MS: ES+ 424.2 (M+1)

[0479] The compounds of the following tabulated Examples (Table Ex13) were prepared analogously to Example 13.1 from the indicated intermediates. Ex. No. Name and Structure Data 13.2 ¹H NMR (400 MHz, DMSO) δ 1.30 (s, 9H), 2.00 (s, 6H), 2.81 - 2.88 (m, 2H), 3.13 - 3.21 (m, 3H), 4.57 - 4.62 (m, 1H), 4.72 - 4.85 (m, 3H), 5.75 (d, J=15.8 Hz, (E)-N-(2-(5-(tert-Butyl)-2,4- 1H), 6.39 (s, 1H), 6.65 (s, 1H), 7.03 (s, dihydroxybenzoyl)isoindolin-4-yl)-4- 1H), 7.21 (d, J=8.3 Hz, 1H), 7.41 - 7.42 (dimethylamino)-N-methylbut-2-enamide (m, 2H), 9.69 (s, 1H), 10.02 - 10.26 (m, Prepared from Intermediate V1-1 and 5- 1H). LCMS (LC-Method 1): 3.34 min, tert-butyl-2,4-dihydroxy-benzoic acid. MS: ES+ 452.2 (M+1) Purified by preparative HPLC using Method Prep-LC-7 13.3 ¹H NMR (400 MHz, DMSO) δ 0.94 - 1.09 (m, 3H), 1.99 - 2.04 (m, 9H), 2.82 - 2.89 (m, 2H), 3.45 - 3.62 (m, 1H), 3.68 - 3.87 (E)-N-(2-(2,4-Dihydroxy-5- (m, 1H), 4.53 - 4.64 (m, 1H), 4.66 - 4.73 methylbenzoyl)isoindolin-4-yl)-4- (m, 1H), 4.81 - 4.89 (m, 2H), 5.63 - 5.73 (dimethylamino)-N-ethylbut-2-enamide (m, 1H), 6.35 - 6.42 (m, 1H), 6.65 (br s, Prepared from Intermediate V1-2 and 2,4- 1H), 6.91 - 7.06 (m, 1H), 7.14 - 7.21 (m, dihydroxy-6-methylbenzoic acid and 1H), 7.32 - 7.49 (m, 2H), 8.18 (s, 1H), purified by preparative HPLC using 9.63 (br s, 1H), 10.09 (br s, 1H). Isolated Method Prep-LC-3 as formate salt. LCMS (LC-Method 1): 2.83 min, MS: ES+ 424.2 (M+1)¹H NMR (400 MHz, DMSO) δ 2.01 (s, 9H), 2.85 - 2.87 (m, 2H), 3.47 - 3.47 (m, 1H), 3.75 - 3.76 (m, 2H), 4.55 - 4.85 (m, 5H), 6.38 (s, 1H), 6.38 (s, 1H), 6.67 (s, (E)-N-(2-(2,4-Dihydroxy-5- 1H), 6.95 - 7.03 (m, 1H), 7.24 (d, J=7.8 methylbenzoyl)isoindolin-4-yl)-4- Hz, 1H), 7.34 (s, 1H), 7.40 - 7.44 (m, (dimethylamino)-N-(2-hydroxyethyl)but-2- 1H), 8.16 (s, 1H), 9.62 (s, 1H), 10.10 (s, enamide 1H). Isolated as formate salt. LCMS Prepared from Intermediate V1-3 and 2,4- (LC-Method 1): 2.30 min, MS: ES+ dihydroxy-5-methylbenzoic acid. Purified 440.2 (M+1) by preparative HPLC using Method Prep- LC-4 ¹H NMR (400 MHz, DMSO) δ 2.01 - 2.04 (m, 9H), 2.89 (s, 2H), 4.56 - 4.64 (m, 3H), 4.80 - 4.85 (m, 2H), 4.98 - 5.15 (m, 1H), 5.78 (s, 1H), 6.40 - 6.41 (m, 1H), 6.80 (s, 1H), 7.03 (d, J=6.1 Hz, 1H), 7.13 (E)-N-(2-(2,4-Dihydroxy-5- - 7.19 (m, 1H), 7.26 - 7.39 (m, 4H), 8.24 methylbenzoyl)isoindolin-4-yl)-4- (s, 1H), 8.44 - 8.49 (m, 2H), 9.71 (s, 1H), (dimethylamino)-N-(pyridin-4- 10.13 (s, 1H). Isolated as formate salt. ylmethyl)but-2-enamide LCMS (LC-Method 1): 1.99 min, MS: Prepared from Intermediate V1-4 and 2,4- ES+ 487.2 (M+1) dihydroxy-5-methylbenzoic acid. Purified by preparative HPLC using Method Prep- LC-4 ¹H NMR (400 MHz, DMSO) δ 2.05 - 2.07 (m, 9H), 2.88 - 2.91 (m, 4H), 3.80 - 3.86 (m, 1H), 4.07 - 4.14 (m, 1H), 4.59 - 4.65 (m, 1H), 4.73 (s, 1H), 4.88 (s, 2H), 5.71 - 5.80 (m, 1H), 6.43 - 6.46 (m, 1H), 6.73 (m, 1H), 7.05 (m, 1H), 7.13 - 7.18 (m, (E)-N-(2-(2,4-Dihydroxy-5- 1H), 7.27 - 7.31 (m, 2H), 7.43 - 7.47 (m, methylbenzoyl)isoindolin-4-yl)-4- 2H), 8.31 (s, 1H), 8.47 - 8.50 (m, 2H), (dimethylamino)-N-(2-(pyridin-4- 9.69 (s, 1H), 10.16 (s, 1H). Isolated as yl)ethyl)but-2-enamide formate salt. LCMS (LC-Method 1): 1.95 min, MS: ES+ 501.2 (M+1)Prepared from Intermediate V1-5 and 2,4- dihydroxy-5-methylbenzoic acid. Purified by preparative HPLC using Method Prep- LC-4 ¹H NMR (400 MHz, DMSO) δ 2.09 (s, 9H), 2.91 (d, J=3.3 Hz, 3H), 3.96 (s, 1H), 4.24 - 4.25 (m, 1H), 4.64 - 4.73 (m, 2H), 4.90 (s, 2H), 5.78 (m, 1H), 6.43 - 6.45 (m, 1H), 6.56 - 6.77 (m, 2H), 6.97 - 7.08 (m, 1H), 7.17 - 7.31 (m, 3H), 7.40 - 7.45 (E)-N-(2-(2,4-Dihydroxy-5- (m, 2H), 7.71 (s, 1H), 8.22 (s, 1H), 8.43 methylbenzoyl)isoindolin-4-yl)-4- - 8.50 (m, 1H), 9.63 - 9.72 (m, 1H), 10.16 (dimethylamino)-N-(2-(pyridin-2- (s, 1H). Isolated as formate salt. LCMS yl)ethyl)but-2-enamide (LC-Method 1): 2.17 min, MS: ES+ Prepared from Intermediate V1-6 and 2,4- 501.2 (M+1) dihydroxy-5-methylbenzoic acid. Purified by preparative HPLC using Method Prep- LC-4 ¹H NMR (400 MHz, DMSO) δ 2.00 - 2.02 (m, 9H) , 2.85 (m, 2H), 3.75 (m, 2H), 4.06 (s, 2H), 4.55 - 4.71 (m, 2H), 4.83 - 4.85 (m, 2H), 5.72 (m, 1H), 6.35 - 6.39 (m, 1H), 6.71 (s, 1H), 6.93 - 7.03 (m, 1H), 7.06 - 7.10 (m, 1H), 7.29 (s, 1H), (E)-N-(2-(2,4-Dihydroxy-5- 7.38 - 7.44 (m, 2H), 7.58 - 7.67 (m, 1H), methylbenzoyl)isoindolin-4-yl)-4- 8.38 - 8.42 (m, 2H), 9.65 (s, 1H), 10.10 (dimethylamino)-N-(2-(pyridin-3- (s, 1H). LCMS (LC-Method 1): 2.04 min, yl)ethyl)but-2-enamide MS: ES+ 501.4 (M+1) Prepared from Intermediate V1-7 and 2,4- dihydroxy-5-methylbenzoic acid. Purified by preparative HPLC using Method Prep- LC-4 ¹H NMR (400 MHz, DMSO) δ 1.86 - 2.04 (m, 12H), 2.75 - 2.96 (m, 3H), 3.67 - 4.17 (m, 2H), 4.29 - 4.36 (m, 1H), 4.40 - 4.59 (m, 2H), 4.69 - 4.82 (m, 1H), 5.55 - 5.71 (m, 1H), 6.21 - 6.26 (m, 1H), 6.44(E)-N-(2-(4,6-Dihydroxy-2,3- - 6.68 (m, 1H), 7.04 - 7.14 (m, 3H), 7.17 dimethylbenzoyl)isoindolin-4-yl)-4- - 7.23 (m, 1H), 7.24 - 7.37 (m, 2H), 7.53 (dimethylamino)-N-(2-(pyridin-2- - 7.62 (m, 1H), 8.33 - 8.37 (m, 1H), 9.16 yl)ethyl)but-2-enamide - 9.20 (m, 2H). LCMS (LC-Method 1): Prepared from Intermediate V1-6 and 4,6- 2.29 min, MS: ES+ 515.3 (M+1) dihydroxy-2,3-dimethylbenzoic acid. Purified by preparative HPLC using Method SFC-1 ¹H NMR (400 MHz, DMSO) δ 1.04 - 1.23 (m, 3H), 1.53 - 1.58 (m, 6H), 1.98 - 2.02 (m, 9H), 2.82 - 2.86 (m, 2H), 3.74 - 3.79 (m, 4H), 4.56 - 4.60 (m, 1H), 4.66 (m, 1H), 4.84 - 4.88 (m, 2H), 5.64 - 5.69 (m, 1H), 6.33 - 6.35 (m, 1H), 6.61 - 6.68 (m, E)-N-(2-(2,4-Dihydroxy-5...

Claims

CLAIMS 1. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, having the structural formula (I), shown below:wherein R2is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; R3is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy, amino-(1- 6C)alkyl or (1-6C)haloalkyl; R4is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (1- 6C)haloalkoxy or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen or (1-6C)alkyl; R5is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; or R4and R5are linked such that, together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl or a heteroaryl, wherein any 4-6 membered heterocyclyl or heteroaryl is optionally substituted by one or more RA, wherein each RAis independently selected from halo, cyano, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl; X is N, CH or CR6, wherein R6is halo, cyano, (1-6C)alkyl or (1-6C)haloalkyl; Y1is -CH2-, C(=O)- or -CHRB, wherein RBis selected from halo, cyano, methyl, methoxy, CF3, - OCF3 or hydroxymethyl; Y2is -CH2-, -C(=O)-, -CHRC-, -CH2-CH2-, -CH2-CHRC- or -CHRC-CH2-, wherein RCis selected from halo, cyano, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1is selected from N, CH, CR7or CR12;A2is selected from N, CH, CR7or CR12; A3is selected from N, CH or CR13; A4is selected from N, CH or CR14; with the proviso that: only one or two of A1, A2, A3or A4can be N; and one of A1and A2is CR7; R7is a group of the formula (IA) or (IB) shown below:(IA) (IB) wherein denotes the point of attachment to A1or A2, R8Ais hydrogen, (1-6C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, heterocyclyl-(1- 4C)alkyl, heteroaryl-(1-4C)alkyl or 8- to 12-membered carbocyclyl, wherein any alkyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3- 6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3- 6C)cycloalkyl or (3-6C)cycloalkoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3- 6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituentsindependently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3- 6C)cycloalkyl or (3-6C)cycloalkoxy; R8is a group of the formula (IA-I) or (IA-II) shown below:(IA-I) (IA-II) wherein denotes the point of attachment, R8Band R8Dare each independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl and -C(O)NR8FR8G, wherein R8Fand R8Gare each independently selected from hydrogen or (1-4C)alkyl; wherein any alkyl moiety present in R8Band / or R8Dis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1- 6C)alkoxy, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any cycloalkyl moiety present in R8Band / or R8Dis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1- 6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; R8Cis selected from hydrogen, halo, (1-6C)alkyl, (1-6C)alkoxy, [(1-4C)alkyl]amino, di-[(1- 4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino- (1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, di[(3-6C)cycloalkyl]amino- (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl-(1-4C)alkyl, aryl-(1- 4C)alkyl, heterocyclyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl; wherein any alkyl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, NR8CAR8CB(wherein R8CAand R8CBare each independently selected from hydrogen and (1-6C)alkyl), (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one ormore substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1- 4C)alkoxy, (3-6C)cycloalkyl or (3-6C)cycloalkoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, NR8CCR8CD(wherein R8CCand R8CDare each independently selected from hydrogen and (1-6C)alkyl), (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any phenyl or 4- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl or (3-6C)cycloalkoxy; or R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl, wherein any 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; R8Eis selected from the group consisting of hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, wherein any alkyl moiety present in R8Eis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3- 6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; and wherein any cycloalkyl moiety present in R8Eis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1- 6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl or 4- to 6-membered heterocyclyl; R12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, (3-6C)cycloalkyl, wherein any (1- 2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1- 2C)alkoxy, or R12is -(CHRp)f-Z12, wherein Rp is hydrogen or methyl; f is 0 or 1; and Z12is -OR20, -NR21R22, -C(O)NR21R22or -NR23C(O)R24;wherein R20is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRq)e-(3-7C)cycloalkyl, -(CHRq)e-phenyl, -(CHRq)e-[4 to 6-membered heterocyclyl] or -(CHRq)e-[5 or 6 membered heteroaryl], wherein Rqis hydrogen or methyl; and e is 0 or 1; R21and R22are each independently selected from hydrogen, (1-6C)alkyl, (2- 6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRr)d-(3-7C)cycloalkyl, -(CHRr)d- phenyl, -(CHRr)d-[4 to 6-membered heterocyclyl] or -(CHRr)d-[5 or 6 membered heteroaryl], wherein Rris hydrogen or methyl; and d is 0 or 1; or R21and R22are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; R23is hydrogen or (1-2C)alkyl; R24is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRs)c-(3-7C)cycloalkyl, -(CHRs)c-phenyl, -(CHRs)c-[4 to 6-membered heterocyclyl] or -(CHRs)c-[5 or 6 membered heteroaryl], wherein Rs is hydrogen or methyl; and c is 0 or 1; wherein each of R20, R21, R22, R23or R24or any ring formed when R21and R22are linked, is optionally substituted with one or more RD; R13is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1- 2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1- 2C)alkoxy, or R13is -(CHRo)h-Z13,wherein Rois hydrogen or methyl; h is 0 or 1; and Z13is -OR25, -NR26R27, -C(O)NR26R27or -NR28C(O)R29; wherein R25is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRn)i-(3-7C)cycloalkyl, -(CHRn)i-phenyl, -(CHRn)i-[4 to 6-membered heterocyclyl] or -(CHRn)i-[5 or 6 membered heteroaryl], wherein Rnis hydrogen or methyl; and i is 0 or 1; R26and R27are each independently selected from hydrogen, (1-6C)alkyl, (2- 6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRm)j-(3-7C)cycloalkyl, -(CHRm)j- phenyl, -(CHRm)j-[4 to 6-membered heterocyclyl] or -(CHRm)j-[5 or 6 membered heteroaryl], wherein Rmis hydrogen or methyl; and j is 0 or 1; or R26and R27are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; R28is hydrogen or (1-2C)alkyl; R29is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRl)k-(3-7C)cycloalkyl, -(CHRl)k-phenyl, -(CHRl)k-[4 to 6-membered heterocyclyl] or -(CHRl)k-[5 or 6 membered heteroaryl], wherein Rl is hydrogen or methyl; and k is 0 or 1; wherein each of R25, R26, R27, R28or R29or any ring formed when R26and R27are linked, is optionally substituted with one or more RD;R14is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1- 2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1- 2C)alkoxy, or R14is -(CHRk)m-Z14, wherein Rkis hydrogen or methyl; m is 0 or 1; and Z14is -OR30, -NR31R32, -C(O)NR31R32or -NR33C(O)R34; wherein R30is (1-4C)alkyl, (3-7C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRj)o-(3-7C)cycloalkyl, -(CHRj)o- [4 to 6-membered heterocyclyl] or -(CHRj)o-[5 or 6 membered heteroaryl], wherein Rjis hydrogen or methyl; and o is 0 or 1; R31and R32are each independently selected from hydrogen, (1-6C)alkyl, (2- 6C)alkanoyl, (3-7C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRi)p-(3-7C)cycloalkyl, -(CHRi)p-[4 to 6-membered heterocyclyl] or -(CHRi)p-[5 or 6 membered heteroaryl], wherein Ri is hydrogen or methyl; and p is 0 or 1; or R31and R32are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; R33is hydrogen or (1-2C)alkyl; R34is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, a carbon-linked 4 to 6- membered heterocyclyl, a 5 or 6 membered heteroaryl, -(CHRh)q-(3-7C)cycloalkyl, -(CHRh)q-[4 to 6-membered heterocyclyl] or -(CHRh)q-[5 or 6 membered heteroaryl], wherein Rh is hydrogen or methyl; and q is 0 or 1;wherein each of R30, R31, R32, R33or R34, or any ring formed when R31and R32are linked, is optionally substituted with one or more RD; and wherein each RDis independently selected from the group consisting of oxo, halo, cyano, hydroxy, (1-4C)alkyl, or a group: -L1-X1-Q1wherein: L1is absent or (1-2C)alkylene; X1is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, - S(O)0-2-, -C(O)-N(R15)-, -N(R15)-C(O)-, -NR15-, -N(R15)-C(O)-NR15-, -SO2N(R15)-, or - N(R15)SO2-, where each R15is independently selected from hydrogen or (1-4C)alkyl; and Q1is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2- 4C)alkynyl, or (3-6C)cycloalkyl.

2. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1, wherein R2is hydrogen, halo, hydroxy, (1-4C)alkyl, (1-4C)alkoxy or (1-4C)haloalkyl.

3. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 or 2, wherein R3is hydrogen or methyl.

4. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R4is hydrogen, halo, hydroxy, (1-4C)alkyl, (1- 4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy or NR4AR4B, wherein R4Aand R4Bare each independently selected from hydrogen or (1-4C)alkyl.

5. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R5is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl (e.g., n-propyl or i-propyl), butyl (e.g., n-butyl, i-butyl or t-butyl), methoxy or CF3.

6. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1-3, wherein R4and R5are linked such that, together with the atoms to which they are attached, they form a 5-membered heterocyclyl comprising 1 or 2 nitrogen atoms or a 5-membered heteroaryl comprising 1 or 2 nitrogen atoms, wherein any 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted by one, two or three RA. 7 A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein each RAis independently selected from fluoro, chloro, hydroxy, oxo, methyl or ethyl.

8. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein X is N, CH, C-Cl, C-F, C-Br, C-CN, C-CH3, C- CH2CH3, C-CH2F, C-CHF2 or C-CF3.

9. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein Y1is -CH2- and / or Y2is -CH2- or -CH2-CH2-.

10. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein: A1is selected from N, CH, CR7or CR12; A2is selected from N, CH, CR7or CR12; A3is selected from N, CH or CR13; A4is selected from N, CH or CR14; with the proviso that: only one of A1, A2, A3or A4can be N;one of A1and A2is CR7; A3cannot be CR13when A4is CR14; and A4cannot be CR14when A3is CR13.

11. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8Ais hydrogen, (1-4C)alkyl, hydroxy-(1-2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6-membered cycloalkyl, aryl, 4- to 6-membered heterocyclyl, heteroaryl, 4- to 6-membered cycloalkyl-(1-2C)alkyl, aryl-(1-2C)alkyl, 4- to 6-membered heterocyclyl-(1-2C)alkyl, heteroaryl-(1-2C)alkyl or 8- to 10-membered carbocyclyl, wherein any alkyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, (4- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl.

12. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8Ais hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxyethyl, methoxyethane, phenyl, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1-2C)alkyl, pyridine-(1-2C)alkyl, morpholine-(1-2C)alkyl, tetrahydropyran-(1-2C)alkyl, or dihydroindene, wherein any alkyl moiety present in R8Ais optionally substituted by one substituent selected from chloro, fluoro, hydroxy, methoxy or phenyl; wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl or carbocyclyl moiety present in R8Ais optionally substituted by one substituent selected from chloro, fluoro, hydroxy, methyl, methoxy or phenyl.

13. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8Band R8Dare each independently selected from the group consisting of hydrogen, fluoro, chloro or methyl.

14. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8Cis selected from hydrogen, halo, (1-4C)alkyl, (1- 4C)alkoxy, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1- 4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, 4- to 6-membered cycloalkyl-(1-4C)alkyl, aryl-(1- 4C)alkyl, 4- to 6-membered heterocyclyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, NR8CAR8CB(wherein R8CAand R8CBare each independently selected from hydrogen and (1-3C)alkyl), (4- 6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any phenyl or 5- to 6- membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4-6C)cycloalkyl or (4-6C)cycloalkoxy; and wherein any alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, NR8CCR8CD(wherein R8CCand R8CDare each independently selected from hydrogen and (1-4C)alkyl), (4-6C)cycloalkoxy, phenyl or 5- to 6-membered heterocyclyl; and wherein any phenyl or 5- to 6-membered heterocyclyl is optionally further substituted by one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4-6C)cycloalkyl or (4-6C)cycloalkoxy.

15. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8Cis selected from hydrogen, methyl, -CH2- NR8C1R8C2, -CH2-N(R8C1)(3C)cycloalkyl, NR8C1R8C2, (1-2C)alkoxy-(1-2C)alkyl, 4- to 6-membered nitrogen-containing heterocyclyl-(1-2C)alkyl or nitrogen-containing heteroaryl-(1-2C)alkyl, wherein R8C1and R8C2are each independently selected from hydrogen, methyl and ethyl, wherein any alkyl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy or NH2; andwherein any alkoxy, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy or NH2.

16. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8cis selected from hydrogen, methyl, -CH2-NH2, - CH2-NMe2, -CH2-NEt2, -CH2-N(Me)Et, CH2-N(Me)cyclopropyl, -NH2, -NMe2, (1-2C)alkoxy-(1- 2C)alkyl, pyrrolidine-(1-2C)alkyl, morpholine-(1-2C)alkyl or azetidine-(1-2C)alkyl, wherein any alkoxy, heterocyclyl or heteroaryl moiety present in R8Cis optionally substituted with two substituents independently selected from fluoro, chloro, hydroxy or methyl.

17. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R8Aand R8Dare linked such that, together with the atoms to which they are attached, they form a 5-membered heterocyclyl, wherein any 5-membered heterocyclyl is optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy, CHF2 or CF3.

18. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R12is selected from cyano, halo, (1-2C)alkyl, (1- 2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R12is -(CHRp)f-Z12, wherein Rp is hydrogen or methyl; f is 0 or 1; and Z12is -OR20or -NR21R22; wherein R20is (1-3C)alkyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl or a 5 or 6 membered heteroaryl,R21and R22are each independently selected from hydrogen, (1-2C)alkyl, (2- 3C)alkanoyl, (4-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl; or R21and R22are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; wherein each of R20, R21or R22or any ring formed when R21and R22are linked, is optionally substituted with one or two RD.

19. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R13is selected from cyano, halo, (1-2C)alkyl, (1- 2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R13is -(CHRo)h-Z13, wherein Ro is hydrogen or methyl; h is 0 or 1; and Z13is -OR25or -NR26R27; wherein R25is (1-3C)alkyl, (3-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6- membered heterocyclyl or a 5 or 6 membered heteroaryl, R26and R27are each independently selected from hydrogen, (1-2C)alkyl, (2- 3C)alkanoyl, (4-6C)cycloalkyl, phenyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl, or R26and R27are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclyl; wherein each of R25, R26or R27or any ring formed when R26and R27are linked, is optionally substituted with one or two RD.

20. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein R14is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, wherein any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R14is -(CHRk)m-Z14, wherein Rkis hydrogen or methyl; m is 0 or 1; and Z14is -OR30or -NR31R32; wherein R30is (1-3C)alkyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl, R31and R32are each independently selected from hydrogen, (1-2C)alkyl, (2- 3C)alkanoyl, (3-6C)cycloalkyl, a carbon-linked 4 to 6-membered heterocyclyl or a 5 or 6 membered heteroaryl, or R31and R32are linked, such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; wherein each of R30, R31or R32, or any ring formed when R31and R32are linked, is optionally substituted with one or two RD.

21. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein each RDis independently selected from the group consisting of oxo, chloro, fluoro, cyano, hydroxy, methyl, or a group: -L1-X1-Q1wherein: L1is absent or methylene; X1is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -NH- or NMe-; and Q1is selected from the group consisting of hydrogen, (1-2C)alkyl, (2-3C)alkenyl, (2- 3C)alkynyl, or (3-6C)cycloalkyl.

22. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the preceding claims, wherein the compound is selected from any one of the following: (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(diethylamino)-N-((1-methyl-1H-pyrazol-4- yl)methyl)but-2-enamide; (E)-4-(3,3-Difluoropyrrolidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)but-2- enamide; ((E)-4-(3,3-Difluoroazetidin-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)but-2- enamide; N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl) acrylamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-N-(2-(2, 4-Dihydroxy-5-methylbenzoyl) isoindolin-4-yl)-4-morpholinobut-2-enamide; N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(5-Chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylacrylamide;(E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-4-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylacrylamide; N-Benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)acrylamide; N-Benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)acrylamide; (E)-N-(2-(2,4-Dihydroxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-phenethylbut-2-enamide; (E)-N-(2-(2-Chloro-4,6-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3,3-dimethylindoline-5-carbonyl)isoindolin-4-yl)-N- methylbut-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-ethylbut-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2- hydroxyethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(pyridin-4- ylmethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-4- yl)ethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-2- yl)ethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-3- yl)ethyl)but-2-enamide;(E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(pyridin-2- yl)ethyl)but-2-enamide; E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2-(tetrahydro-2H- pyran-4-yl)ethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-(2- methoxyethyl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(5-Chloro-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-1H-indole-5-carbonyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(5-Bromo-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-(trifluoromethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-Cyano-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-6-(trifluoromethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-Benzoylisoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-2-methoxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2-(Difluoromethyl)-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2-Chloro-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-1H-indazole-5-carbonyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(4-(Difluoromethyl)-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-fluoro-2,4-dihydroxybenzoyl)isoindolin-4-yl)but-2-enamide;(E)-4-(Dimethylamino)-N-(2-(6-hydroxybenzo[d]isoxazole-5-carbonyl)isoindolin-4-yl)but-2- enamide; (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(4-Amino-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-ethyl-2,4-dihydroxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-isopropylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(3-Chloro-4-(difluoromethoxy)-6-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-N-(2-(4-(Difluoromethoxy)-2-hydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-N-(2-(3-(tert-Butyl)-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindolin-4-yl)-N-methylbut-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-(trifluoromethyl)benzoyl)isoindolin-4-yl)-N-methylbut- 2-enamide; (E)-N-(2-(3-Chloro-4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut- 2-enamide; N-[2-(2,4-Dihydroxy-5-methyl-benzoyl)isoindolin-4-yl]-N-[2-(4-pyridyl)ethyl]prop-2-enamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-N-(2-(1-methylpyrrolidin-3- yl)ethyl)acrylamide;N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)acrylamide; N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)acrylamide; (E)-N-[2-(2,4-Dihydroxy-5-methyl-benzoyl)isoindolin-4-yl]-4-(dimethylamino)-N-indan-2-yl-but-2- enamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-N-(2-morpholinoethyl)acrylamide; N-(2-(2,4-Dihydroxy-6-methylbenzoyl)isoindolin-4-yl)-N-methylacrylamide; (E)-N-[2-(2,4-Dihydroxybenzoyl)isoindolin-4-yl]-4-(dimethylamino)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-methylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-fluoro-4-hydroxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-hydroxypicolinoyl)isoindolin-4-yl)but-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-methoxybenzoyl)isoindolin-4-yl)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-(trifluoromethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-methoxybut-2-enamide; 1-(2-(2,4-Dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-3-(2-(dimethylamino)ethylidene)pyrrolidin- 2-one; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1-methylpiperidin- 4-yl)acrylamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-ethylbut-2- enamide; N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-N-(2-methoxyethyl)acrylamide; N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-N-methylacrylamide;(E)-N-(2-(5-(tert-Butyl)-2,4-dihydroxybenzoyl)-5-chloroisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(5-Chloro-2-(2, 4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethyl amino)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)isoindolin-4-yl)- N-methylbut-2-enamide; (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- ethylbut-2-enamide; (E)-N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(ethyl(methyl)amino)-N- methylbut-2-enamide; (E)-N-(7-Chloro-2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(7-Chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl)isoindolin-4-yl)-N-methyl acrylamide; (E)-N-(5-Chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N- methylbut-2-enamide; (E)-N-(2-(3-Chloro-2-fluoro-4,6-dihydroxybenzoyl) isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(3-Chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-ethylbut- 2-enamide; N-(2-(3-Chloro-4,6-dihydroxy-2-methylbenzoyl) isoindolin-4-yl)-N-ethyl acrylamide; N-(2-(3-Chloro-2-fluoro-4,6-dihydroxybenzoyl) isoindolin-4-yl)-N-methylacrylamide; N-(2-(2,4-Dihydroxy-5-methylbenzoyl)-6-(2-(dimethylamino) ethoxy) isoindolin-4-yl)-N- methylacrylamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-2,3-dimethyl-1H-indole-5-carbonyl) isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-2-methyl-1H-indole-5-carbonyl) isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(6-hydroxy-3-methyl-1H-indole-5-carbonyl) isoindolin-4-yl)-N- methylbut-2-enamide;(E)-4-(Dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl) isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-4-methoxy-5-methylbenzoyl)isoindolin-4-yl)-N- methylbut-2-enamide; (E)-N-(2-(3-(tert-Butyl)-2-fluoro-6-hydroxy-5-(hydroxymethyl)benzoyl)isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(3-(Aminomethyl)-5-(tert-butyl)-6-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-N- methylacrylamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-5-chloroisoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindolin-4-yl)-N- methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(5-ethyl-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylbut- 2-enamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(5-Ethyl-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; (E)-N-(2-(3-(tert-Butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(3-(tert-Butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl) isoindolin-4-yl)-N-methyl acrylamide; (E)-N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(5-Chloro-2-(5-chloro-2-hydroxy-4-methoxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N- methylbut-2-enamide;(E)-N-(5-Chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(4-Fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(5-Chloro-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(6-Hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(6-Hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl) isoindolin-4-yl)-N-methyl acrylamide; N-(6-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N- methylacrylamide; N-(7-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin- 2-yl)-N-methylacrylamide; N-(6-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin- 3-yl)-N-methylacrylamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-4-fluoro-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-enamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(6-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) acrylamide;(E)-N-(2-(3-Chloro-6-hydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(6-(5-(tert-Butyl)-2-hydroxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-4- (dimethylamino)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-(dimethylamino)- N-methylbut-2-enamide; (E)-N-(5-Chloro-2-(4-hydroxy-3-isopropylbenzoyl) isoindolin-4-yl)-4-(dimethylamino) but-2- enamide; (E)-N-(5-Chloro-2-(4-hydroxy-3-isopropylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylacrylamide; N-(6-(2-(Dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-ynamide; (E)-N-(5-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-4-(dimethyl amino)-N-methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-fluoro-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(2-(5-(tert-Butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(3-Chloro-2-fluoro-6-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-N-methylacrylamide; N-(5-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-N-methyl acrylamide; (E)-4-(Dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5-methylisoindolin-4-yl)- N-methylbut-2-enamide; N-(2-(4-Fluoro-2-hydroxy-5-isopropylbenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(6-Chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide;N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(6-(2-(Dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylacrylamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)-N-methylacrylamide; (E)-N-(7-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridin- 2-yl)-N-methylbut-2-enamide; N-(7-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-2- yl)-N-methylacrylamide; N-(7-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7- naphthyridin-2-yl)-N-methylacrylamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-N-methylacrylamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1- methylpiperidin-4-yl) acrylamide; (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(2-(4,6-Dihydroxy-2,3-dimethylbenzoyl)-6-methylisoindolin-4-yl)-4-(dimethylamino)-N- methylbut-2-enamide; (E)-N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin- 3-yl)-N-methylbut-2-enamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N- methylacrylamide; N-(2-(2-Hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1- methylpyrrolidin-3-yl)acrylamide; ((E)-N-(5-Chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindolin-4-yl)-4- (dimethylamino)but-2-enamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-4- (dimethylamino)but-2-enamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3- yl)acrylamide;(E)-N-(2-(3-Chloro-6-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbut- 2-enamide; (E)-N-(7-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-4- (dimethylamino)-N-methylbut-2-enamide; N-(7-Chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl) isoindolin-4-yl)-N-methyl acrylamide; (E)-4-(Dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-N-methylbut-2-enamide; N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-ynamide; (E)-N-(5-Chloro-2-(3-chloro-4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)but-2- enamide; (E)-N-(5-Chloro-2-(4-hydroxy-2,3-dimethylbenzoyl) isoindolin-4-yl)-4-(dimethylamino) but-2- enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-3-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-N-methylbut-2-enamide; (E)-4-(Dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- N-methylbut-2-enamide; N-(2-(4-Hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(1-methylpiperidin-4- yl)acrylamide; (E)-4-(Dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methoxy-5,6,7,8- tetrahydro-1,6-naphthyridin-3-yl)-N-methylbut-2-enamide; ((E)-4-(Dimethylamino)-N-(6-(4-hydroxy-3-isopropylbenzoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-N-methylbut-2-enamide; (E)-N-(2-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- N-methylbut-2-enamide; N-(6-(3-Chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3- yl)but-2-ynamide.

23. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1-22, in admixture with a pharmaceutically acceptable diluent or carrier.

24. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1-22, or a pharmaceutical composition as defined in claim 23, for use in therapy.

25. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1-22, or a pharmaceutical composition as defined in claim 23: (i) for use in the treatment of cancer; (ii) for use in the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with another anticancer agent (e.g., a chemotherapeutic agent, an immune checkpoint inhibitor, an immune stimulator or DNA damage repair modulator); (iii) for use in the treatment of a triplet repeat disorder.

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