Inhibitor Compounds

Abstract

The present invention relates to compounds of formula (I) that target MLH1 or MLH1 and PMS2 proteins, which are components of the DNA mismatch repair (MMR) process. [Formula 1] JPEG2024528693000171.jpg70170 Formula (I), wherein R6, Y1, Y2, A1, A2, A3, A4, R11, R12, R13 and R14 are each as defined herein. The invention also relates to methods for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders, such as cancer, and other diseases or conditions in which MLH1 or MLH1 and PMS2 activity is implicated.

Description

[Technical Field]

[0001] [preface] The present invention relates to several compounds that function as selective inhibitors of MLH1 or MLH1 and PMS2 protein activity. The compounds of the present invention can be used to treat, at least in part, diseases or conditions mediated by inappropriate MLH1 and PMS2 activity, such as cancer. The present invention further relates to the use of the compounds as pharmaceuticals, methods for making them, and pharmaceutical compositions containing them. [Background technology]

[0002] Cancer is caused by alterations in cell proliferation. What exactly causes cells to become malignant and grow in a controlled and unregulated manner has been the focus of intensive research over the past decades. Such studies have identified the most important pathways and associated molecular targets 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 the normal DNA replication process. Base pair mismatches occur when an incorrect nucleotide is inserted into a newly synthesized DNA strand and circumvents the proofreading function of DNA polymerase. Indel loops commonly occur in association with microsatellites, which are highly polymorphic short, repetitive DNA sequences distributed throughout prokaryotic and eukaryotic genomes. Normally, in microsatellites, the template and primer strands are prone to slippage (dissociation and reannealing) during replication, which can generate loop structures and discordant numbers of repeat units between the template and newly synthesized strands.

[0004] DNA mismatch repair is a bidirectional excision and resynthesis system that initiates with a defined strand break 3'- or 5'-to the mismatch; the excision tract extends just beyond the mismatch. MMR can be divided into four steps: 1) mismatch recognition by MSH proteins; 2) recruitment of MLH proteins, which link the mismatch recognition signal to the site of DNA strand break initiation; 3) excision of the erroneous DNA strand; and 4) resynthesis of the excision gap using the remaining DNA strand as a template [1]. MMR is a highly conserved biological pathway. In humans, the MMR pathway is initiated by mismatch recognition by hMutSα (MSH2-MSH6) or hMutSβ (MSH2-MSH3). Binding of hMutSα or hMutSβ to the mismatch site leads to the recruitment of MutLα (MLH1-PMS2) to form a ternary complex, whose protein-protein and protein-DNA interactions are modulated by ATP / ADP cofactors. Proliferating cell nuclear antigen (PCNA) may play a role in recruiting MMR proteins to the vicinity of replication forks [1]. PCNA can also activate the latent endonuclease activity of eukaryotic MutLα proteins. After DNA cleavage, exonuclease 1 (EXO1) is recruited, which excises the newly synthesized DNA strand, and the DNA excision gap is resynthesized by DNA polymerase δ (Polδ). If DNA resynthesis is complete, the remaining nick is ligated by DNA ligase, restoring double-strand integrity [2]. Consistent with this function, MMR is an important tumor suppressor pathway that reduces sporadic cancers by up to 40%. Furthermore, individuals with germline mutations in MMR genes develop a cancer predisposing state.

[0005] Lynch syndrome (LS, formerly named hereditary nonpolyposis 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 malignant lesions at several extracolonic sites, including the endometrium, ovaries, stomach, and small intestine, among others. [3] LS has an autosomal dominant inheritance pattern and is caused by germline mutations in the MMR genes MLH1, MSH2, MSH6, or PMS2. Gene expression from one wild-type allele is sufficient for adequate MMR activity until a second hit inactivates the wild-type allele, resulting in MMR deficiency.

[0006] Congenital mismatch repair disorder (CMMRD) syndromes are distinct childhood cancer predisposition syndromes resulting from biallelic germline mutations in one of four MMR genes, MLH1, MSH2, MSH6, or PMS2. Patients can have homozygous biallelic alterations or heterozygous alterations in the MMR genes.

[0007] MMR-abnormal cancers are generally characterized by the accumulation of DNA mutations at a rate faster than normal cells and other tumors; for example, CMMRD tumors typically have a hypermutated phenotype (>250 substitution mutations / Mb) [4]. MMR deficiency also results in an increase or decrease in microsatellite repeat length, termed microsatellite instability (MSI). Cancers with greater than 40% microsatellite mutations (positive for two or more of five routinely tested microsatellite markers) are described as MSI-high (MSI-H). Tumors lacking MSI are microsatellite stable (MSS), while those with less than 40% microsatellite mutations (one of the five markers indicating microsatellite instability) are MSI-low (MSI-L) [5]. MSI analysis is a widely used diagnostic biomarker for MMR-deficient tumors, and MSI status is associated with a high prevalence of frameshift (FS) mutations, which can occur due to insertions / deletions within coding microsatellites. In addition to altering downstream protein functions, FS creates new amino acid sequences that act as substrates for antigen processing and presentation [6], stimulating CD8+ T cell activation (class I) and CD4+ T cell "helper" function (class II).

[0008] Cancers with a higher number of neoantigens are more prone to immune surveillance and are more likely to respond to immunotherapy [7]; a higher neoantigen load is associated with total lymphocyte infiltration, TILs, memory T cells, and survival in colorectal cancer [8, 9]. This characteristic supports the rationale for immunotherapy-based therapeutic strategies [6]. Consistent with this concept, immune checkpoint inhibitors now represent an important therapeutic advance in the treatment of MMR-abnormal cancers. PD-1 inhibitors, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), have been approved by the US Food and Drug Administration (FDA) for patients with MMR-D or MSI-H metastatic CRC based on their significant survival benefit. The CTLA-4 inhibitor ipilimumab (Yervoy) has been approved for use in combination with nivolumab for the treatment of patients with MMR-D or MSI-H CRC previously treated with chemotherapy. Importantly, the FDA approved the use of pembrolizumab in MMR-D / MSI-H cancers, regardless of histological tumor type

[10] .

[0009] It is now accepted that clinical response to immune checkpoint inhibitors requires the presence of tumor neoantigens and the infiltration of T cells that recognize these neoantigens. Higher neoantigen burden is associated with a better 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 associated with TMB, and several large studies have confirmed that high TMB correlates with enhanced checkpoint inhibitor response and improved overall survival in several tumor types, such as urothelial carcinoma

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

[19] .

[0010] Germano et al. recently proposed that MMR inactivation by silencing MLH1 increases TMB, resulting in a "dynamic mutational profile" and persistent neoantigen regeneration in vitro and in vivo. This induces immune surveillance and, particularly in combination with immune checkpoint inhibition in mouse models, results in tumor growth control

[20] . Similar results have been observed with silencing MSH2

[21] .

[0011] Guan et al. and Lu et al. reported that MLH1 deficiency leads to the release of cytosolic DNA and activation of the cGAS-STING pathway and IFN-β production. Guan et al. demonstrated that loss of MLH1 leads to DNA hyperexcision, RPA depletion, chromosomal instability, and cytosolic DNA accumulation. Lu et al. reported that cytosolic DNA sensing by the cGAS-STING pathway contributes to the clinical benefit of immunotherapy in patients with MMR-deficient tumors. Together, these reports suggest that by suppressing MMR activity, activation of the cGAS-STING pathway can induce beneficial immune activation.

[0012] Thus, there is robust biological and clinical evidence highlighting the need for inhibitors targeting MLH1 or MLH1 and PMS2 proteins, the most important components of DNA-MMR, to restore antitumor immune responses.

[0013] Thus, the present invention provides methods for the treatment of cancer by binding to and modulating the function of the DNA-MMR components MLH1 or MLH1 and PMS2 using small molecules as single agents and in combination with immunotherapeutics, other DNA damage response pathway modulators and / or standard of care chemotherapeutics.

[0014] Outside of the cancer field, triplet repeat disorders include more than 30 human neurodegenerative and neuromuscular genetic disorders, 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 generally found in different regions of several genes, and their expansions can cause disease through various loss-of-function and gain-of-function pathways, for example, by interfering with the expression or characteristics of gene products or by affecting splicing or antisense regulation. Several mechanisms have been proposed to contribute to repeat instability, including errors during DNA replication, meiotic recombination, transcription, DNA repair, and chromatin remodeling, which can occur at various stages of the cell cycle. There is evidence that a functional MMR pathway is required to maintain the stability of microsatellite sequences: for example, Msh2- / - transgenic mice carrying a copy of human HD exon 1 (containing a CAG repeat) show a reduced expansion of the introduced (CAG)n repeat when compared to their Msh2+ / +HD exon 1 mouse counterparts

[22] .

[0015] Thus, there is a further need for compounds that target the MLH1 or MLH1 and PMS2 components of the DNA-MMR process for the treatment of triplet repeat disorders.The present invention was made with the foregoing in mind. <References> 1. Martin-Lopez, JV 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. 4. 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 5. Sehgal, R., et al., Lynch syndrome: an updated review. Genes (Basel), 2014. 5(3): p. 497-507 6. Willis, J.A., et al., Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate. Clin Cancer Res, 2019. 7. Gubin, M.M. and R.D. Schreiber, CANCER. The odds of immunotherapy success. Science, 2015. 350(6257): p. 158-9. 8. Kloor, M. and M. von Knebel Doeberitz, The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer, 2016. 2(3): p. 121-133. 9. Giannakis, M., et al., Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep, 2016. 17(4): p. 1206. 10. 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. 11. Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015. 372(26): p. 2509-20. 12. 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. 13. Van Allen, E.M., et al., Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science, 2015. 350(6257): p. 207-211. 14. 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. 15. 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. 16. 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. 17. 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. 18. 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. 19. 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. 20. Germano, G., et al., Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature, 2017. 552(7683): p. 116-120. 21. 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. 22. 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. 23. Guan J., et al., MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1 activates the cGAS-STING pathway. Cancer Cell. 2021, 39 (1), 109 - 121, 24. 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

[0016] According to a first aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0017] 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.

[0018] According to a further aspect of the present invention, there is provided a method for inhibiting MLH1 activity or MLH1 and PMS2 activity in vitro or in vivo, said method comprising the step of contacting a cell with an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0019] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which MLH1 activity or MLH1 and PMS2 activity is associated in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, 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 proliferative disorder in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0021] 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 the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0022] According to a further aspect of the present invention, there is provided a method of treating a triplet disorder (e.g., Huntington's disease (HD), myotonic dystrophy type 1 (DM1), Fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar degeneration (SCAs)) in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0023] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

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

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

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

[0027] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in treating a triplet disorder. In particular embodiments, the triplet 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 degeneration (SCAs).

[0028] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activity).

[0029] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which MLH1 activity or MLH1 and PMS2 activity is associated.

[0030] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

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

[0032] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a triplet disorder. In particular embodiments, the triplet 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 degeneration (SCAs).

[0033] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the inhibition of MLH1 activity or MLH1 and PMS2 activity.

[0034] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which MLH1 activity or MLH1 and PMS2 activity is associated.

[0035] According to a further aspect of the present invention there is provided a process for preparing a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0036] 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 by a process for preparing a compound as defined herein.

[0037] According to a further aspect of the present invention there is provided a novel intermediate, as defined herein, suitable for use in any one of the synthetic methods described herein.

[0038] 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 invention are useful in the treatment of any cancer in which mismatch repair inhibition and / or cGAS-STING pathway activation is beneficial. Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal 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 tumor, cervical cancer, colorectal cancer, Cowden disease, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's 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 tumors, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia Disease, 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 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis types 1 and 2, nevoid basal cell carcinoma syndrome, oral or oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma , pituitary tumors, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi's or soft tissue), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, vulvar cancer, Waldenström's macroglobulinemia, Werner's syndrome, Wilms' tumor, and xeroderma pigmentosum). Particular cancers of interest include hematological cancers, such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-esophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0039] <Probe Compound> The present invention also relates to the discovery of a new series of probe compounds that efficiently bind to the ATP-binding site of the GHKL-family protein MLH1 or MLH1 and PMS2. These probe compounds can be used in assays and methods for evaluating the binding affinity of test compounds to the ATP-binding site of MLH1 or MLH1 and PMS2. Furthermore, these probe compounds can be used to determine the location and / or content of MLH1 or MLH1 and PMS2 in biological samples.

[0040] Thus, in another aspect, the present invention provides a compound comprising R 12 or R 13 is LQ or L as defined herein x Provided is a probe compound of formula I, as defined herein, or a salt thereof, wherein X is a group.

[0041] In another aspect, the present invention provides a method of synthesizing a probe compound of formula I, or a salt thereof, as defined herein.

[0042] In another aspect, the present invention provides the use of a probe compound of formula I, or a salt thereof, in a displacement assay to determine the binding affinity of a test molecule to the ATP-binding site of a target protein. In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a detailed embodiment, the target protein is MLH1.

[0043] In another aspect, the present invention provides a probe compound of formula I, or a salt thereof, for use in a displacement assay to determine the binding affinity of a test molecule to the ATP-binding site of a target protein. In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a detailed embodiment, the target protein is MLH1.

[0044] In another aspect, the present invention provides an assay for determining the binding affinity of a test molecule to an ATP-binding site of a target protein, the assay comprising: (i) incubating a test molecule with a target protein in the presence of a probe compound of Formula I, or a salt thereof, as defined herein; (ii) determining whether the probe compound of formula I displaces the ATP binding site of the target protein; Includes. In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a particular embodiment, the target protein is MLH1.

[0045] In another aspect, the present invention provides a method for determining the binding affinity of a test molecule to an ATP-binding site of a target protein, the assay comprising: (i) incubating a test molecule with a target protein in the presence of a probe compound of Formula I, or a salt thereof, as defined herein; (ii) determining whether the probe compound of formula I displaces the ATP binding site of the target protein; Includes.

[0046] In another aspect, the present invention provides an assay for determining the location and / or abundance of a target protein present in a biological sample, the assay comprising: (i) contacting a biological sample with a probe compound of Formula I, or a salt thereof, as defined herein; (ii) determining the location and / or amount of the compound of formula I present in the biological sample by detecting the location and / or intensity of the detectable moiety of the compound of formula I present in the sample; Includes.

[0047] In another aspect, the present invention provides an assay for determining the location and / or abundance of a target protein present in a biological sample, the assay comprising: (i)R 12 or R 13is L as defined herein. x contacting a biological sample with a probe compound of formula I, or a salt thereof, wherein -X is a group; (ii) reacting in situ within a biological sample with a functional group X present in a compound of formula I to form R 12 or R 13 contacting the biological sample with a detection moiety, Q, as defined herein, or a compound of the formula Q-L2-Y, which is capable of forming a compound of formula I, wherein one of is a group LQ, as defined herein; (iii) determining the location and / or amount of the compound of formula I present in the biological sample by detecting the location and / or intensity of the detection moiety Q of the probe compound of formula I present in the sample; Includes.

[0048] In another aspect, the present invention provides a method for determining the location and / or abundance of a target protein present in a biological sample, the method comprising: (i) contacting a biological sample with a probe compound of Formula I, or a salt thereof, as defined herein; (ii) determining the location and / or amount of the compound of formula I present in the biological sample by detecting the location and / or intensity of the detection moiety Q of the probe compound of formula I present in the sample; Includes.

[0049] In another aspect, the present invention provides a method for determining the location and / or abundance of a target protein present in a biological sample, the method comprising: (i)R 12 or R 13 is L as defined herein. x contacting a biological sample with a probe compound of formula I, or a salt thereof, wherein -X is a group; (ii) reacting in situ within a biological sample with a functional group X present in the probe compound of formula I to form R 12 or R 13contacting the biological sample with a detection moiety, Q, as defined herein, or a compound of the formula Q-L2-Y, which is capable of forming a compound of formula I, wherein one of is a group LQ, as defined herein; (iii) determining the location and / or amount of the compound of formula I present in the biological sample by detecting the location and / or intensity of the detection moiety Q of the compound of formula I present in the sample; Includes.

[0050] In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a particular embodiment, the target protein is MLH1, i.e. the probe is selective for MLH1.

[0051] Features, including optional, suitable and preferred features, with respect to one aspect of the invention may also be features, including optional, suitable and preferred features, with respect to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0052] [Definition] Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0053] References to "treating" or "treatment" shall be understood to include prevention as well as the alleviation of established symptoms of a condition. Thus, "treating" a situation, disorder, or condition or "treatment" of a situation, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the situation, disorder, or condition occurring in a person who may be afflicted with or predisposed to the situation, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the situation, disorder, or condition; (2) inhibiting the situation, disorder, or condition, i.e., (in the case of maintenance treatment) arresting, reducing, or delaying the onset of the disease or its recurrence or at least one of its clinical or subclinical symptoms; or (3) relieving or attenuating the disease, i.e., causing regression of the situation, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0054] "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" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated. For example, in humans or other mammals, it should be understood that a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or the therapeutically effective amount can be the amount required by the guidelines of the U.S. Food and Drug Administration (FDA) or a corresponding foreign regulatory agency for a particular disease and subject to be treated. It should be understood that the determination of appropriate dosage forms, dosage amounts, and administration routes is within the level of ordinary skill in the pharmaceutical and medical fields.

[0055] As used herein, alone or in combination with one or more other terms, "subject(s)" and "patient(s)" refer to animals (e.g., mammals), particularly humans. Suitably, "subject(s)" and "patient(s)" may be non-human animals (e.g., livestock or household pets) or humans.

[0056] As used herein, alone or in combination with one or more other terms, "pharmaceutically acceptable" generally refers to a material that is chemically and / or physically compatible with other ingredients (e.g., as with respect to a formulation), and / or generally physiologically compatible with its recipient (e.g., a subject, etc.).

[0057] As used herein, the term "alkyl" includes straight-chain and branched-chain alkyl groups. Reference to an individual alkyl group, such as "propyl," is specific for the straight-chain version only, and reference to an individual branched-chain alkyl group, such as "isopropyl," is specific for the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl.

[0058] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0059] 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 straight-chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms, such as methylene (-CH-), the ethylene isomers (-CH(CH)- and -CHCH-), the propylene isomers (-CH(CH)CH-, -CH(CHCH)-, -C(CH)-, and -CHCHCH-), pentylene (-CHCHCHCHCHCH-), and the like.

[0060] The term "alkyenyl" refers to straight- and branched-chain alkyl groups containing two or more carbon atoms and at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl, and but-2,3-enyl, including all possible geometric (E / Z) isomers.

[0061] The term "alkynyl" refers to straight- and branched-chain alkyl groups containing two or more carbon atoms and at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0062] "(m-nC)cycloalkyl" means a saturated hydrocarbon ring system containing m to n carbon atoms. Exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicyclo[2.2.1]heptyl.

[0063] The term "alkoxy" refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and t-butoxy.

[0064] The term "haloalkyl," as used herein, refers 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 -CHF, -CHF, and -CF.

[0065] The term "halo" or "halogeno" refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably fluoro and chloro.

[0066] 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 about 3 to 12 (suitably 3 to 7) ring atoms. Bicyclic carbocyclic rings contain 6 to 17 member atoms, suitably 7 to 12 member atoms in the ring. Bicyclic carbocyclic ring(s) can be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, and spiro[3.3]heptanyl.

[0067] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain about 3 to 12 (suitably 3 to 7) ring atoms, with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms, suitably 7 to 12 member atoms in the ring. Bicyclic heterocyclic ring(s) can be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. In the case of sulfur-containing heterocycles, sulfur-oxide heterocycles containing SO or SO groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide, etc. The heterocycle can contain one or two oxo (=O) or thioxo (=S) substituents.Suitable values ​​for a heterocyclyl group bearing one or two oxo (=O) or thioxo (=S) substituents are, 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, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As would be understood by one skilled in the art, any heterocycle can be linked to another group by any suitable atom, for example, a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring linked by the ring nitrogen.

[0068] "Bridged ring system" means a ring system in which two rings share two or more atoms, see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, 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.

[0069] By "spiro bicyclic ring system," we mean that the two ring systems share one common spiro carbon atom, i.e., the heterocyclic ring is linked to an additional carbocyclic or heterocyclic ring by 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]heptane, 2-oxa-6-azaspiro[3.3]heptane, 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.

[0070] As used herein, alone or in combination with another term or terms, "aromatic" refers to monocyclic and polycyclic ring systems containing 4n+2 π-electrons, where n is an integer. Aromatic should be understood to refer to and include ring systems containing only carbon atoms (i.e., "aryl") as well as ring systems containing at least one heteroatom selected from N, O, or S (i.e., "heteroaromatic" or "heteroaryl"). Aromatic ring systems may be substituted or unsubstituted.

[0071] As used herein, alone or in combination 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 π system. As used herein, non-aromatic refers to ring systems containing only carbon atoms as well as ring systems containing at least one heteroatom selected from N, O, or S, and the non-aromatic ring systems they comprise may be substituted or unsubstituted.

[0072] The term "heteroaryl" or "aromatic heterocycle" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, e.g., a 5- and 6-membered fused ring or a bicyclic structure formed from two 6-membered fused rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, more usually up to two, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring 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. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be fewer than five.

[0073] 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, quinazolyl. nyl, 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, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other ring(s) is non-aromatic, saturated or partially saturated, provided that 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.

[0074] Examples of 5-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.

[0075] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0076] Bicyclic heteroaryl groups include, for example: 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 aromatic heterocycle containing 1, 2, or 3 ring heteroatoms; and The group may be a group selected from a cyclopentyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms.

[0077] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-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.

[0078] Specific 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, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0079] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a specific embodiment, the aryl is phenyl.

[0080] This specification also uses some compound terms to describe groups containing two or more functional groups. Such terms are understood by those skilled in the art. For example, (3-6C)cycloalkyl(m-nC)alkyl includes (m-nC)alkyl substituted with (3-6C)cycloalkyl.

[0081] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and groups, structures, or molecules that are not substituted. 1 "One / any CH, CH, CH group or heteroatom (i.e., NH) within the group is optionally substituted" means that R 1 Suitably, it means that (any) one of the hydrogen radicals of the group is replaced by the associated defined group.

[0082] When optional substituents are selected from "one or more" groups, it is understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. In some embodiments, one or more refers to one, two, or three. In other embodiments, one or more refers to one or two. In particular embodiments, one or more refers to one.

[0083] The phrase "compounds of the invention" means, both generically and specifically, the compounds disclosed herein.

[0084] When used herein in connection with a measurable value, such as an amount or duration, "about" is meant to encompass a reasonable variation in the value, for example, allowing for experimental error in determining said value.

[0085] <Compound> In one aspect, the present invention provides a compound of structural formula (I), shown below: [ka] [In the formula, R 2 is hydrogen or fluoro; R 4 is hydrogen or fluoro; R 6is a (1-6C)alkyl, (3-8C)cycloalkyl, or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O, or S; or a group having a structure according to formula (A) shown below: [ka] (In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is (3-8C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, or (1-3C)haloalkoxy; Y1 is -CH2- or -C(=O)-; Y2 is -CH2-, -C(=O)-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, cyano, methyl, methoxy, CF, -OCF or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1 is N, CH or CR 11 Selected from; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; provided that only one or two of A1, A2, A3 or A4 may be N; R11 is cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or -(CHR z ) a -Z 11 (In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 , -C(O)NR 16 R 17 or -NR 18 C(O)R 19 and; R 15 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-7C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 8-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 is hydrogen, (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-7C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w )c -[5- or 6-membered heteroaryl]; R w is hydrogen or methyl, and c is 0 or 1. or R 16 and R 17 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 18 is hydrogen or (1-2C) alkyl; R 19 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR x ) d -(3-7C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4- to 8-membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl]; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 16 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a (possibly substituted with ); R 12 The following options are available: (i)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (ii)R 11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 12 is -(CHR v ) d -Z 12 (In the formula, R v is hydrogen or methyl; d is 0 or 1; Z 12 -OR 20 , -NR 21 R 22 , -C(O)NR 21 R 22 or -NR 23 C(O)R 24 and; R 20 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4- to 8-membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], and R u is hydrogen or methyl, and e is 0 or 1; R 21 and R 22is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl]; R q is hydrogen or methyl, and f is 0 or 1; or R 21 and R 22 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 23 is hydrogen or (1-2C) alkyl; R 24 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4- to 8-membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], and R p is hydrogen or methyl, and g is 0 or 1; R 20 , R 21 , R 22 , R 23 Or R 24 , or R 21 and R 22 Each of any rings formed when R are linked may contain one or more R a (possibly replaced by Selected from one of; R 13 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted with one or more halo or (1-2C)alkoxy; or R 13 is -(CHR o ) h -Z 13 (In the formula, R o is hydrogen or methyl; h is 0 or 1; Z 12 -OR 25 , -NR 26 R 27 , -C(O)NR 26 R 27 or -NR 28 C(O)R 29 and; R 25 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4- to 8-membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], and R n is hydrogen or methyl, and i is 0 or 1; R 26 and R 27 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHRm ) j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl]; R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 28 is hydrogen or (1-2C) alkyl; R 29 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4- to 8-membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], and R l is hydrogen or methyl, and k is 0 or 1; R 25 , R 26 , R 27 , R 28 Or R 29 or R 26 and R 27 Each of any rings formed when R are linked may contain one or more R a (possibly substituted with ); R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 14 is -(CHRk ) m -Z 14 (In the formula, R k is hydrogen or methyl; m is 0 or 1; Z 12 -OR 30 , -NR 31 R 32 , -C(O)NR 31 R 32 or -NR 33 C(O)R 34 and; R 30 is (1-4C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4- to 8-membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], and R j is hydrogen or methyl, and o is 0 or 1; R 31 and R 32 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR i ) p -(3-7C)cycloalkyl, -(CHR i ) p -[4- to 8-membered heterocyclyl] or -(CHR i ) p -[5- or 6-membered heteroaryl]; R i is hydrogen or methyl, and p is 0 or 1. or R 31 and R 32 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 33is hydrogen or (1-2C) alkyl; R 34 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR h ) q -(3-7C)cycloalkyl, -(CHR h ) q -[4- to 8-membered heterocyclyl] or -(CHR h ) q -[5- or 6-membered heteroaryl], and R h is hydrogen or methyl, and q is 0 or 1; R 30 , R 31 , R 32 , R 33 Or R 34 , or R 31 and R 32 Any ring formed when R are linked may be formed by one or more R a In some cases replaced by; Each R a is oxo, halogen, cyano, hydroxy, (1-4C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -N(R 14 )-C(O)-NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl; Q 1 is (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl, then Q 1 is one or more Q a and each Q a is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, or (1-3C)haloalkoxy; R 12 or R 13 One of the cases is: -LQ or -L x is an -X group, L is a linker; L x is a linker; X is a functional group; and Q is a detection moiety, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0086] In one aspect, the present invention provides a compound of structural formula (I), shown below: [ka] [In the formula, R 2 is hydrogen or fluoro; R 4 is hydrogen or fluoro; R 6 is a (1-6C)alkyl, (3-8C)cycloalkyl, or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O, or S; or a group having a structure according to formula (A) shown below: [ka] (In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is (3-8C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, or (1-3C)haloalkoxy; Y1 is -CH2- or -C(=O)-; Y2 is -CH2-, -C(=O)-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, cyano, methyl, methoxy, CF, -OCF or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1 is N, CH or CR 11 Selected from; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; provided that only one or two of A1, A2, A3 or A4 may be N; R 11 is cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or -(CHR z )a -Z 11 (In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 , -C(O)NR 16 R 17 or -NR 18 C(O)R 19 and; R 15 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-7C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 8-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 is hydrogen, (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-7C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl]; R w is hydrogen or methyl, and c is 0 or 1. or R 16 and R 17are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 18 is hydrogen or (1-2C) alkyl; R 19 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR x ) d -(3-7C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4- to 8-membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl]; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 16 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a (possibly substituted with ); R 12 The following options are available: (iii)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (iv)R 11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 12 is -(CHR v ) d -Z 12 (In the formula, R v is hydrogen or methyl; d is 0 or 1; Z 12 -OR 20 , -NR 21 R 22 , -C(O)NR 21 R 22 or -NR 23 C(O)R 24 and; R 20 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4- to 8-membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], and R u is hydrogen or methyl, and e is 0 or 1; R 21 and R 22 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f-[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl]; R q is hydrogen or methyl, and f is 0 or 1; or R 21 and R 22 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 23 is hydrogen or (1-2C) alkyl; R 24 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4- to 8-membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], and R p is hydrogen or methyl, and g is 0 or 1; R 20 , R 21 , R 22 , R 23 Or R 24 , or R 21 and R 22 Each of any rings formed when R are linked may contain one or more R a (possibly replaced by Selected from one of; R 13 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted with one or more halo or (1-2C)alkoxy; or R 13 is -(CHR o )h -Z 13 (In the formula, R o is hydrogen or methyl; h is 0 or 1; Z 12 -OR 25 , -NR 26 R 27 , -C(O)NR 26 R 27 or -NR 28 C(O)R 29 and; R 25 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4- to 8-membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], and R n is hydrogen or methyl, and i is 0 or 1; R 26 and R 27 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl]; R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 28 is hydrogen or (1-2C) alkyl; R 29 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4- to 8-membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], and R l is hydrogen or methyl, and k is 0 or 1; R 25 , R 26 , R 27 , R 28 Or R 29 or R 26 and R 27 Each of any rings formed when R are linked may contain one or more R a (possibly substituted with ); R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 14 is -(CHR k ) m -Z 14 (In the formula, R k is hydrogen or methyl; m is 0 or 1; Z 12 -OR 30 , -NR 31 R 32 , -C(O)NR31 R 32 or -NR 33 C(O)R 34 and; R 30 is (1-4C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4- to 8-membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], and R j is hydrogen or methyl, and o is 0 or 1; R 31 and R 32 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR i ) p -(3-7C)cycloalkyl, -(CHR i ) p -[4- to 8-membered heterocyclyl] or -(CHR i ) p -[5- or 6-membered heteroaryl]; R i is hydrogen or methyl, and p is 0 or 1. or R 31 and R 32 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 33 is hydrogen or (1-2C) alkyl; R 34 is (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR h ) q -(3-7C)cycloalkyl, -(CHR h ) q-[4- to 8-membered heterocyclyl] or -(CHR h ) q -[5- or 6-membered heteroaryl], and R h is hydrogen or methyl, and q is 0 or 1; R 30 , R 31 , R 32 , R 33 Or R 34 , or R 31 and R 32 Any ring formed when R are linked may be formed by one or more R a In some cases replaced by; Each R a is oxo, halogen, cyano, hydroxy, (1-4C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -N(R 14 )-C(O)-NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl; R 12 or R 13 One of the cases is: -LQ or -L xis an -X group, L is a linker; L x is a linker; X is a functional group; and Q is a detection moiety, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0087] In a further aspect, the present invention provides a compound of formula I, as defined herein, wherein R 2 , R 4 , R 6 , Y1, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 each have one of the definitions set forth above, except that R 12 or R 13 One of: -LQ or -L x is an -X group, L is a linker; L x is a linker; X is a functional group; Q is a detection moiety.

[0088] Certain compounds of the present invention include, for example, compounds of formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, unless otherwise specified, wherein R 2 , R 4 , R 6 , Y1, Y2, A1, A2, A3, A4, L, L x Each of X, Q and any associated substituents has any of the meanings defined above or in any of the following paragraphs (1) to (125): (1)R 2 is hydrogen; (2)R 2 is fluoro; (3)R 4is hydrogen; (4)R 4 is fluoro; (5)R 6 is a (1-6C)alkyl, (3-6C)cycloalkyl, or 4- to 6-membered heterocyclyl ring containing one heteroatom selected from N, O, or S; or a group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is (3-7C)cycloalkyl, phenyl, heterocyclyl, or heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, or (1-3C)haloalkoxy; (6)R 6 is a (1-6C)alkyl, (3-6C)cycloalkyl, or 4- to 6-membered heterocyclyl ring containing one heteroatom selected from N, O, or S; or a group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is (3-8C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9are independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, or (1-3C)haloalkoxy; (7)R 6 is a (1-6C) alkyl or group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is (3-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C) alkyl, (1-2C) alkoxy, (1-2C) haloalkyl, or (1-2C) haloalkoxy; (8)R 6 is a (1-4C) alkyl or group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or (1-2C) alkyl; n is 1 or 2; R 8 is (3-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C) alkyl, (1-2C) alkoxy, (1-2C) haloalkyl, or (1-2C) haloalkoxy; (9)R6 is a (1-4C) alkyl or group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or methyl; n is 1; R 8 is (4-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C) alkyl, (1-2C) alkoxy, (1-2C) haloalkyl, or (1-2C) haloalkoxy; (10)R 6 is a (1-3C) alkyl or group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or methyl; n is 1; R 8 is cyclohexyl, phenyl, 6-membered heterocyclyl, 6-membered heteroaryl, each of which may be selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; (11)R 6 is a group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or methyl; n is 1; R 8 is cyclohexyl, phenyl, 6-membered heterocyclyl, 6-membered heteroaryl, each of which may be selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; (12)R 6 is a group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or methyl; n is 1; R 8 is cyclohexyl, phenyl, 6-membered heterocyclyl, pyridyl, each of which may be selected from one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; (13)R 6 is a group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or methyl; n is 1; R 8 is cyclohexyl, phenyl, pyridyl, each of which may be one or more R 9 optionally substituted with; each R 9 are independently selected from the group consisting of fluoro, chloro, methyl, or methoxy; (14)R 6 is a group having a structure according to formula (A) shown below: [ka] [In the formula, R 7 is hydrogen or methyl; n is 1; R 8 is one or more R 9 is phenyl optionally substituted with 9 are independently selected from the group consisting of fluoro, chloro, methyl, or methoxy; (15) Y1 is -CH2-; (16) Y1 is —C(═O)—; (17) Y2 is -CH2-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, cyano, methyl, CF3, or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; (18) Y2 is -CH2-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, methyl, or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; (19) Y2 is -CH2-, -CH2-CH2-, or -CH2-CHR y2b - and;R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; (20) Y2 is -CH2- or -CH2--CH2-; (21) Y2 is -CH2-; (22) Y2 is -CH2-CH2-; (23) A1 is CH or CR 11Selected from; (24) A1 is CH; (25) A1 is CR 11 is; (26) A2 is CH or CR 12 Selected from; (27) A2 is N; (28) A2 is CH; (29) A2 is CR 12 is; (30) A3 is CH or CR 13 Selected from; (31) A3 is N; (32) A3 is CH; (33) A3 is CR 13 is; (34) A4 is CH or CR 14 Selected from; (35) A4 is N; (36) A4 is CH; (37) A4 is CR 14 is; (38) A1 is N, CH or CR 11 Selected from; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; provided that only one of A1, A2, A3 or A4 can be N; (39) A1 is CH or CR 11 and; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; However, only one of A2, A3 or A4 can be N; (40) A1 is CR 11 and; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; However, only one of A2, A3 or A4 can be N; (41) A1 is CR 11 and; A2 is selected from N or CH; A3 is N, CH or CR 13 Selected from; A4 is selected from N or CH; However, only one of A2, A3 or A4 can be N; (42) A1 is CR 11 and; A2 is CH; A3 is CH or CR 13 and; A4 is CH; (43) A1 is CR 11 and; A2 is CH; A3 is CH; A4 is CH; (44) A1 is CH; A2 is CR 12 and; A3 is CH; A4 is CH; (45) A1 is CH; A2 is CH; A3 is CR 13 and; A4 is CH; (46)R 11 is cyano, halo or (1-2C)alkyl optionally substituted by one or more halo or (1-2C)alkoxy; or -(CHR z ) a -Z 11 [In the formula, Rz is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 , -C(O)NR 16 R 17 or -NR 18 C(O)R 19 and; R 15 is (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl]; R w is hydrogen or methyl, and c is 0 or 1. or R 16 and R 17 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 6-membered heterocyclic ring; R 18is hydrogen or (1-2C) alkyl; R 19 is (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR x ) d -(3-6C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4- to 6-membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl]; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 16 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (47)R 11 is cyano, fluoro, chloro or (1-2C)alkyl optionally substituted by one or more fluoro, chloro or (1-2C)alkoxy; or -(CHR z ) a -Z 11 [In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 , -C(O)NR 16 R 17 or -NR18 C(O)R 19 and; R 15 is (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl]; R w is hydrogen or methyl, and c is 0 or 1. or R 16 and R 17 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 6-membered heterocyclic ring; R 18 is hydrogen or (1-2C) alkyl; R 19 is (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or -(CHR x ) d -(3-6C)cycloalkyl; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 16 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (48)R 11 is cyano or -(CHR z ) a -Z 11 [In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 or -NR 18 C(O)R 19 and; R 15 is (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl]; R w is hydrogen or methyl, and c is 0 or 1. or R 16 and R 17 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 6-membered heterocyclic ring; R 18 is hydrogen or (1-2C) alkyl; R 19 is (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or -(CHR x ) d -(3-6C)cycloalkyl; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 16 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (49)R 11 is -(CHR z ) a -Z11 [In the formula, R z is hydrogen; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 or -NR 18 C(O)R 19 and; R 15 is (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl]; R w is hydrogen or methyl, and c is 0 or 1. or R 16 and R 17 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 6-membered heterocyclic ring; R 18 is hydrogen or (1-2C) alkyl; R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 16 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (50)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 , -NR 16 R 17 or -NR 18 C(O)R 19 and; R 15 is (3-6C)cycloalkyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 is hydrogen and R 17is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], and R w is hydrogen or methyl, and c is 0 or 1; or R 16 and R 17 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 6-membered heterocyclic ring; R 18 is hydrogen or (1-2C) alkyl; R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R x is hydrogen or methyl, and d is 0 or 1; R 15 , R 17 , R 18 Or R 19 , or R 16 and R 17 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (51)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 or -NR 16 R 17 and; R 15 is (3-6C)cycloalkyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 is hydrogen and R 17 is selected from (3-6C)cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl; R 15 or R 17 Each of the a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (52)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 or -NR 16 R 17 and; R 15 is (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b-phenyl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 is hydrogen and R 17 is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], and R w is hydrogen or methyl, and c is 0 or 1; R 15 or R 17 Each of the a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (53)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen or methyl; a is 0 or 1; Z 11 -OR 15 or -NR 16 R 17 and; R 15is (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4- to 6-membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], and R y is hydrogen or methyl, and b is 0 or 1; R 16 is hydrogen and R 17 is (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], and R w is hydrogen or methyl, and c is 0 or 1; R 15 or R 17 Each of the a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (54)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen; a is 0 or 1; Z 11 is -NR 16 R17 and; R 16 is hydrogen and R 17 is (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], and R w is hydrogen or methyl, and c is 0 or 1; R 17 is one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (55)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen; a is 0 or 1; Z 11 -NHR 17 and; R 17 teeth; (i) a group of formula (A), (B), (C) or (D): [ka] (In the formula, W1 is OR w1a or NR w1a R w1b Selected from R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl; R W1C, R W1D and R W1E is selected from hydrogen or methyl, or R W1C and R W1D Or R W1D and R W1E are linked together with the carbon atoms to which they are attached so that they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which may be joined by one or more R a In some cases replaced by; W2 is O, NR w2 , S, or S(O)2; R w2 is selected from hydrogen, (1-4C) alkyl or (2-4C) alkanoyl; Each of formulas (B), (C) and (D) may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below); (ii) Bridged versions of formulas (C) and (D) above, optionally selected from one of formulas (E) through (J) below: [ka] wherein Y4 is selected from -CH2-, -CH2CH2-; Each of formulas (E), (F), (G), (H) and (J) may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below); (iii) a group of formula (K), (L) or (M): [ka] (In the formula, R W3 is selected from hydrogen or (1-2C) alkyl; W3, W4 and W5 are N or CR w4 Selected from R w4 is hydrogen, halo, (1-2C) alkyl or (1-2C) alkoxy; One of W6 and W7 is N and the other is CR w5 and W8 is N or CR w5 and R w5 is hydrogen, halo, (1-2C) alkyl or (1-2C) alkoxy; W9, W 10 , W 11 and W 12 is N or CR w6 Selected from R w6 is hydrogen, halo, (1-2C) alkyl or (1-2C) alkoxy; provided that W, W 10 , W 11 and W 12 (where only one or two of the is selected from the following. (56)R 11 is -(CHR z ) a -Z 11 [In the formula, R z is hydrogen; a is 0 or 1; Z 11 -NHR 17 and; R 17 teeth; (i) a group of formula (A), (B), (C) or (D): [ka] (In the formula, W1 is OR w1a or NR w1a R w1b Selected from R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl; R W1C , R W1D and R W1Eis selected from hydrogen, or R W1C and R W1D Or R W1D and R W1E are linked together with the carbon atoms to which they are attached so that they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which may be joined by one or more R a In some cases replaced by; W2 is O, NR w2 or S(O)2, and R w2 is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of formulas (B), (C) and (D) may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below); (ii) Bridged versions of formulas (C) and (D) above, optionally selected from one of formulas (E) through (J) below: [ka] wherein Y4 is selected from -CH2-, -CH2CH2-; Each of formulas (E), (F), (G), (H) and (J) may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below); (iii) a group of formula (K), (L) or (M): [ka] (In the formula, R W3 is selected from hydrogen or (1-2C) alkyl; W3, W4 and W5 are selected from N or CH; one of W6 and W7 is N and the other is CH, and W8 is N or CH; W9, W 10 , W 11 and W 12 is N or CR w6 Selected from R w6 is hydrogen, halo, (1-2C) alkyl or (1-2C) alkoxy; provided that W, W 10 , W 11 and W 12 (exactly one of the is N) is selected from the following. (57)R 12 The following options are available: (i)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (ii)R 11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 12 is -(CHR v ) d -Z 12 [In the formula, R v is hydrogen or methyl; d is 0 or 1; Z 12 -OR 20 , -NR 21 R 22 , -C(O)NR 21 R22 or -NR 23 C(O)R 24 and; R 20 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4- to 8-membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], and R u is hydrogen or methyl, and e is 0 or 1; R 21 and R 22 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl]; R q is hydrogen or methyl, and f is 0 or 1; or R 21 and R 22 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 23 is hydrogen or (1-2C) alkyl; R 24 is (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR p )g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4- to 8-membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], and R p is hydrogen or methyl, and g is 0 or 1; R 20 , R 21 , R 22 , R 23 Or R 24 , or R 21 and R 22 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below. Selected from one of; (58)R 12 The following options are available: (i)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (ii)R 11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R12 is -(CHR v ) d -Z 12 [In the formula, R v is hydrogen or methyl; d is 0 or 1; Z 12 -OR 20 , -NR 21 R 22 , -C(O)NR 21 R 22 or -NR 23 C(O)R 24 and; R 20 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4- to 8-membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], and R u is hydrogen and e is 0 or 1; R 21 and R 22 is hydrogen, (1-6C) alkyl, (3-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl]; R q is hydrogen or methyl, and f is 0 or 1; or R 21 and R22 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 23 is hydrogen or methyl; R 24 is (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4- to 8-membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], and R p is hydrogen or methyl, and g is 0 or 1; R 20 , R 21 , R 22 , R 23 Or R 24 , or R 21 and R 22 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below. Selected from one of; (59)R 12 The following options are available: (i)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (ii)R11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 12 is -(CHR v ) d -Z 12 [In the formula, R v is hydrogen; d is 0 or 1; Z 12 -OR 20 , -NR 21 R 22 , -C(O)NR 21 R 22 or -NR 23 C(O)R 24 and; R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; R 21 and R 22 are each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; or R 21 and R 22 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 23 is hydrogen; R 24 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; R 20 , R 21 , R22 Or R 24 , or R 21 and R 22 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below. Selected from one of; (60)R 12 The following options are available: (i)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (ii)R 11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 12 is -(CHR v ) d -Z 12 [In the formula, R v is hydrogen; d is 0 or 1; Z 12 -OR 20 , -NR 21 R 22 or -C(O)NR 21 R 22 and; R 20is (1-4C) alkyl; R 21 and R 22 are each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; or R 21 and R 22 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 20 , R 21 Or R 22 , or R 21 and R 22 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below. Selected from one of; (61)R 12 The following options are available: (i)R 11 Ga-(CHR z ) a -Z 11 When R is a group, 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or (ii)R 11 Ga-(CHR z ) a -Z 11 If it is not a group, R 12 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy. Selected from one of; (62)R 13 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted with one or more halo or (1-2C)alkoxy; or R 13 is -(CHR o ) h -Z 13 [In the formula, R o is hydrogen or methyl; h is 0 or 1; Z 12 -OR 25 , -NR 26 R 27 , -C(O)NR 26 R 27 or -NR 28 C(O)R 29 and; R 25 is (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4- to 8-membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], and R n is hydrogen or methyl, and i is 0 or 1; R 26 and R 27 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m )j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl]; R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 28 is hydrogen or methyl; R 29 is (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4- to 8-membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], and R l is hydrogen or methyl, and k is 0 or 1; R 25 , R 26 , R 27 Or R 29 or R 26 and R 27 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (63)R 13 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted with one or more halo or (1-2C)alkoxy; or R 13 is -(CHR o ) h -Z 13 [In the formula, R o is hydrogen or methyl; h is 0 or 1; Z 12 -OR 25 , -NR 26 R 27 , -C(O)NR 26 R 27 or -NR 28 C(O)R 29 and; R 25 is (1-4C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR n ) i -(3-7C)cycloalkyl, or -(CHR n ) i -[4- to 8-membered heterocyclyl], and R n is hydrogen or methyl, and i is 0 or 1; R 26 and R 27 is hydrogen, (1-6C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR m ) j -(3-7C)cycloalkyl, or -(CHR m ) j -[4- to 8-membered heterocyclyl]; R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 28 is hydrogen or methyl; R 29 is (1-6C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR l ) k-(3-7C)cycloalkyl, or -(CHR l ) k -[4- to 8-membered heterocyclyl], and R l is hydrogen or methyl, and k is 0 or 1; R 25 , R 26 , R 27 Or R 29 or R 26 and R 27 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (64)R 13 is selected from halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted with one or more halo or (1-2C)alkoxy; or R 13 is -(CHR o ) h -Z 13 [In the formula, R o is hydrogen or methyl; h is 0 or 1; Z 12 -OR 25 , -NR 26 R 27 , or -C(O)NR 26 R 27 and; R 25 is (1-4C) alkyl, carbon-linked 4- to 8-membered heterocyclyl, or -(CHR n ) i -[4- to 8-membered heterocyclyl], and R n is hydrogen or methyl, and i is 0 or 1; R 26 and R 27is hydrogen, (1-6C) alkyl, carbon-linked 4- to 8-membered heterocyclyl, or -(CHR m ) j -[4- to 8-membered heterocyclyl]; R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 25 , R 26 , R 27 or R 26 and R 27 Each of any rings formed when R are linked may contain one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (65)R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 14 is -(CHR k ) m -Z 14 [In the formula, R k is hydrogen or methyl; m is 0 or 1; Z 12 -OR 30 , -NR 31 R 32 , -C(O)NR 31 R 32 or -NR 33 C(O)R 34 and; R 30is (1-4C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4- to 8-membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], and R j is hydrogen or methyl, and o is 0 or 1; R 31 and R 32 is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR i ) p -(3-7C)cycloalkyl, -(CHR i ) p -[4- to 8-membered heterocyclyl] or -(CHR i ) p -[5- or 6-membered heteroaryl]; R i is hydrogen or methyl, and p is 0 or 1. or R 31 and R 32 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 33 is hydrogen or methyl; R 34 is (1-6C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR h ) q -(3-7C)cycloalkyl, -(CHR h ) q -[4- to 8-membered heterocyclyl] or -(CHR h ) q -[5- or 6-membered heteroaryl], and R h is hydrogen or methyl, and q is 0 or 1; R 30 , R 31 , R 32 Or R 34 , or R 31 and R 32 Any ring formed when R are linked may be formed by one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (66)R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 14 is -(CHR k ) m -Z 14 [In the formula, R k is hydrogen; m is 0 or 1; Z 12 -OR 30 , -NR 31 R 32 , -C(O)NR 31 R 32 or -NR 33 C(O)R 34 and; R 30 is (1-4C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR j ) o -(3-7C)cycloalkyl, or -(CHR j ) o -[4- to 8-membered heterocyclyl], and R j is hydrogen or methyl, and o is 0 or 1; R 31 and R 32is hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR i ) p -(3-7C)cycloalkyl, or -(CHR i ) p -[4- to 8-membered heterocyclyl]; R i is hydrogen or methyl, and p is 0 or 1. or R 31 and R 32 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 33 is hydrogen or methyl; R 34 is (1-6C) alkyl, (3-7C) cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR h ) q -(3-7C)cycloalkyl, or -(CHR h ) q -[4- to 8-membered heterocyclyl], and R h is hydrogen or methyl, and q is 0 or 1; R 30 , R 31 , R 32 Or R 34 , or R 31 and R 32 Any ring formed when R are linked may be formed by one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (67)R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; or R 14is -(CHR k ) m -Z 14 [In the formula, R k is hydrogen; m is 0 or 1; Z 12 -OR 30 , -NR 31 R 32 , -C(O)NR 31 R 32 or -NR 33 C(O)R 34 and; R 30 is (1-4C) alkyl, carbon-linked 4- to 8-membered heterocyclyl, or -(CHR j ) o -[4- to 8-membered heterocyclyl], and R j is hydrogen or methyl, and o is 0 or 1; R 31 and R 32 is hydrogen, (1-6C) alkyl, carbon-linked 4- to 8-membered heterocyclyl, or -(CHR i ) p -[4- to 8-membered heterocyclyl]; R i is hydrogen or methyl, and p is 0 or 1. or R 31 and R 32 are linked together with the nitrogen atom to which they are attached so that they form a 4- to 8-membered heterocyclic ring; R 33 is hydrogen; R 34 is (1-6C) alkyl, carbon-linked 4- to 8-membered heterocyclyl, or -(CHR h ) q -[4- to 8-membered heterocyclyl], and R h is hydrogen or methyl, and q is 0 or 1; R 30 , R 31 , R 32 Or R 34 , or R 31 and R 32Any ring formed when R are linked may be formed by one or more R a In some cases replaced by; R a is as defined above or in any one of paragraphs (69) to (73) or (121) to (125) below; (68)R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted with one or more halo or (1-2C)alkoxy; (69)Each R a is oxo, halogen, cyano, hydroxy, (1-4C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; (70)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl, or (3-6C) cycloalkyl; (71)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14から R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen or (1-2C) alkyl; (72)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L1 does not exist; X 1 is absent, or -O-, -C(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14から R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen or (1-2C) alkyl; (73)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 does not exist; X 1 is absent or -O-, -C(O)-, -C(O)-N(R 14 )- or -NR 14から R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen or (1-2C) alkyl; (121) Each R a is oxo, halogen, cyano, hydroxy, (1-4C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; Q 1 is (1-4C) alkyl or (3-6C) cycloalkyl, Q 1 is one or more Q a and each Q a is independently selected from the group consisting of (1-3C)alkoxy, (1-3C)haloalkyl, or (1-3C)haloalkoxy. (122)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen, (1-3C) alkyl, or (3-6C) cycloalkyl; Q 1 is (1-3C) alkyl or (3-6C) cycloalkyl, Q 1 is one or more Q aand each Q a is independently selected from the group consisting of (1-2C)alkoxy, (1-2C)haloalkyl, or (1-2C)haloalkoxy. (123)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14から R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen or (1-3C) alkyl; Q 1 is (1-3C) alkyl, Q 1 is one or more Q a and each Q a is independently selected from the group consisting of (1-3C)alkoxy. (124)Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 does not exist; X 1 is absent, or -O-, -C(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14)-C(O)- or -NR 14から R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen or (1-3C) alkyl; Q 1 is (1-3C) alkyl, Q 1 is one or more Q a and each Q a is independently selected from the group consisting of (1-2C)alkoxy. (125) Each R a is oxo, halogen, cyano, hydroxy, (1-2C) alkyl, or -L 1 -X 1 -Q 1 basis are independently selected from the group consisting of L 1 does not exist; X 1 is absent or -O-, -C(O)-, -C(O)-N(R 14 )- or -NR 14から R 14 is hydrogen or (1-2C) alkyl; Q 1 is selected from the group consisting of hydrogen or (1-3C) alkyl; Q 1 is (1-3C) alkyl, Q 1 is one or more Q a Each Q is replaced by a is methoxy.

[0089] Probe Compound (74) L is a (2-20C) alkylene linker, and the alkylene chain may be one or more -O-, -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10 optionally further comprising a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (75) L is a (3-20C) alkylene linker, and the alkylene chain may be one or more -O-, -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10 optionally further comprising a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (76) L is a (2-20C) alkylene linker, the alkylene chain having 1 to 8 -O- bonds and / or 1 to 4 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10 further containing a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (77) L is a (3-20C) alkylene linker, the alkylene chain having 1 to 8 -O- bonds and / or 1 to 4 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10further containing a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (78) L is a (2-18C) alkylene linker, the alkylene chain having 1 to 5 -O- bonds located within the alkylene chain and / or at one of its termini; and / or 1 to 4 -C(O)-, -C(O)NR 10 -, -NR 10 optionally further comprising a C(O)—, —C(O)O—, —OC(O)— bond or one piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (79) L is a (3-12C) alkylene linker, the alkylene chain having 1 to 5 -O- bonds located within the alkylene chain and / or at one of its termini; and / or 1 to 4 -C(O)-, -C(O)NR 10 -, -NR 10 optionally further comprising a C(O)—, —C(O)O—, —OC(O)—, or one piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (80) L is a (2-18C) alkylene linker, the alkylene chain having 1 to 5 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)-bond or one piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (81) L is a (3-12C) alkylene linker, the alkylene chain having 1 to 5 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)-bond or one piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (82) L is a (2-18C) alkylene linker, the alkylene chain having 1 to 5 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (83) L is a (3-12C) alkylene linker, the alkylene chain having 1 to 5 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (84) L is a (2-18C) alkylene linker, the alkylene chain having 1-3 -O- bonds and / or 1-3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (85) L is a (3-12C) alkylene linker, the alkylene chain having 1-3 -O- bonds and / or 1-3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (86) L is a (2-18C) alkylene linker, the alkylene chain having one -O- bond and / or one -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (87) L is a (3-12C) alkylene linker, the alkylene chain having one -O- bond and / or one -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (88) L is a (2-17C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10 optionally further containing a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (89) L is a (3-10C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10 optionally further containing a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (90) L is a (2-17C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds located within the alkylene chain and / or at one of its termini; and / or 1 to 3 -C(O)-, -C(O)NR 10 -, -NR 10 further containing a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (91) L is a (3-10C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds located within the alkylene chain and / or at one of its termini; and / or 1 to 3 -C(O)-, -C(O)NR 10 -, -NR 10 further containing a C(O)—, —C(O)O—, —OC(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (92) L is a (2-17C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10 further containing a C(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (93) L is a (3-10C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -, -NR 10further containing a C(O)—, piperazine or triazole ring bond; R 10 is hydrogen or (1-2C)alkyl, and the alkylene chain is optionally substituted by one or more substituents independently selected from halo, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy. (94) L is a (2-17C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (95) L is a (3-10C) alkylene linker, the alkylene chain having 1 to 4 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (96) L is a (2-17C) alkylene linker, the alkylene chain having 1 to 3 -O- bonds and / or 1 to 3 -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (97) L is a (3-10C) alkylene linker, the alkylene chain having one to three -O- bonds and / or one to three -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (98) L is a (2-17C) alkylene linker, the alkylene chain having one -O- bond and / or one -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (99) L is a (3-10C) alkylene linker, the alkylene chain having one -O- bond and / or one -C(O)-, -C(O)NR located within the alkylene chain and / or at one of its termini. 10 -or-NR 10 further containing a C(O)- bond or one piperazine or triazole ring bond, R 10 is hydrogen or (1-2C) alkyl. (100)L is a compound of the formula: -L p1 -X p1 -L p2 -X p2 -L p3 - [In the formula, L p1 is absent or (1-8C) alkylene; X p1 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 selected from C(O)—, —C(O)O—, —OC(O)—, or a piperazine or triazole ring; L p2 is a (1-10C) alkylene or a group of the formula -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a - group, where a is 1 to 10 and b is 2 to 4; X p2is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 selected from C(O)—, —C(O)O—, —OC(O)—, or a piperazine or triazole ring; L p3 is absent or (1-8C) alkylene; R p1 is hydrogen or (1-2C) alkyl; However, X p1 or X p2 is present. (101) L is a group having the formula: -L p1 -X p1 -L p2 -X p2 -L p3 - [In the formula, L p1 is absent or (1-6C) alkylene; X p1 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 selected from C(O)—, —C(O)O—, —OC(O)—, or a piperazine or triazole ring; L p2 is a (1-10C) alkylene or a group of the formula -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a - group, a is 2 to 10, and b is 2 to 4; X p2 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 selected from C(O)—, —C(O)O—, —OC(O)—, or a piperazine or triazole ring; L p3 is absent or (1-6C) alkylene; R p1 is hydrogen or methyl; However, X p1 or X p2 is present. (102) L is a group having the formula: -L p1 -X p1 -L p2 -X p2 -L p3 - [In the formula, L p1 is absent or (2-6C) alkylene; X p1 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 C(O)— or a piperazine or triazole ring; L p2 is a (2-10C) alkylene or a group of the formula -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a - group, a is 2 to 10, and b is 2 to 4; X p2 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 C(O)— or a piperazine or triazole ring; L p3 is absent or (1-6C) alkylene; R p1 is hydrogen or methyl; However, X p1 or X p2 is present. (103) L is a group having the formula: -L p1 -X p1 -L p2 -X p2 -L p3 - [In the formula, L p1is absent or (2-6C) alkylene; X p1 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 C(O)— or a piperazine or triazole ring; L p2 is a (2-6C) alkylene or a group of the formula -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a - group, a is 2 to 10, and b is 2 to 4; X p2 is absent, or -O-, -C(O)-, or -C(O)NR p1 -, -NR p1 C(O)— or a piperazine or triazole ring; L p3 is absent or (2-6C) alkylene; R p1 is hydrogen or methyl; However, X p1 or X p1 is present. (104) L is a group represented by the formula: -L p1 -X p1 -L p2 -X p2 -L p3 - [In the formula, L p1 does not exist; X p1 does not exist; L p2 is absent or is a (2-6C) alkylene or a group of the formula -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a - group, a is 2 to 10, and b is 2 to 4; X p2-O-, -C(O)-, -C(O)NR p1 -, -NR p1 C(O)- or a triazole ring; L p3 is absent or (2-6C) alkylene; R p1 is hydrogen or methyl; However, X p1 or X p2 is present. (105) L is a group having the formula: -L p1 -X p1 -L p2 -X p2 -L p3 - [In the formula, L p1 is (2-6C) alkylene; X p1 -O-, -C(O)NR p1 -, -NR p1 C(O)— or a piperazine or triazole ring; L p1 is a (2-6C) alkylene or a group of the formula -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a - group, a is 2 to 10, and b is 2 to 4; X p2 -O-, -C(O)NR p1 -, -NR p1 C(O)- or a triazole ring; L p3 is (2-6C) alkylene; R p1 is hydrogen or methyl; However, X p1 or X p2 is present. (106) Q is a detection moiety selected from the group consisting of a fluorophore, an oligonucleotide, a biomolecule, a molecular sensor, a protein, or a peptide. (107) Q is a fluorophore. (108) Q is a fluorophore selected from the group consisting of AlexaFluor dyes, cyanine dyes, fluorescein, BODIPY or BODIPY derivatives (e.g., BODIPY TMR), TAMRA, Oregon Green dyes, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red. (109) Q is a fluorophore selected from the group consisting of AlexaFluor-647, AlexaFluor-633, AlexaFluor-594, AlexaFluor-488, cyanine-5B, cyanine-3B, fluorescein, BODIPY or a BODIPY derivative (e.g., BODIPY TMR), TAMRA, Oregon Green 488, Oregon Green 514, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red. (110)X is a functional group capable of reacting with a functional group present in the detection moiety to covalently attach the detection moiety to the compound of formula II. (111)X is a functional group capable of reacting with a functional group present in a detection moiety to covalently attach the detection moiety selected from the group consisting of a fluorophore, an oligonucleotide, a biomolecule, a molecular sensor, a protein, or a peptide to the compound of formula II. (112) X is a functional group X that is capable of reacting with a functional group present in a fluorophore to covalently attach the fluorophore to the compound of formula II. (113) X is a functional group capable of reacting with a functional group present in a fluorophore to covalently attach the fluorophore to a compound of formula II, the fluorophore being as defined above in paragraphs (44) or (45). (114) X is halo, N3, or ethynyl ( [ka] ) is a functional group selected from (115) X is ethynyl ( [ka] ) or N3. (116)L x is a linker group L as defined in any one of paragraphs (10) to (41) above. (117)L x is a (1-8C) alkylene linker, the alkylene chain being provided with one or more -O-, -C(O)NR located within the alkylene chain and / or at one of its termini; 10 -, -NR 10 optionally further comprising a C(O)-, -C(O)O-, -OC(O)- or triazole ring bond; R 10 is hydrogen or (1-2C) alkyl. (118)L x is a (1-8C) alkylene linker, the alkylene chain having one -O-, -C(O)NR located within the alkylene chain and / or at one of its termini; 10 -, -NR 10 optionally further comprising a C(O)-, -C(O)O-, -OC(O)- or triazole ring bond; R 10 is hydrogen or (1-2C) alkyl. (119) Lx is a (1-5C) alkylene linker. (120) Lx is a (1-3C) alkylene linker.

[0090] Appropriately, R 2 is as defined in numbered paragraph (1) above.

[0091] Appropriately, R 4 is as defined in paragraph (3) above.

[0092] Appropriately, R 6is as defined in any one of the above numbered paragraphs (5) to (14). More appropriately, R 6 is as defined in any one of the numbered paragraphs (10) to (14) above. Most suitably, R 6 is as defined in the numbered paragraphs (12), (13) or (14) above.

[0093] Suitably, Y1 is as defined in numbered paragraph (15) or (16). Most suitably, Y1 is as defined in numbered paragraph (15).

[0094] Suitably, Y2 is as defined in any one of numbered paragraphs (17) to (22). More suitably, Y2 is as defined in numbered paragraphs (18), (19), (21) or (22). Most suitably, Y2 is as defined in numbered paragraphs (21) or (22).

[0095] Suitably, A1 is as defined in any one of numbered paragraphs (23) to (25). Most suitably, A1 is as defined in numbered paragraph (23).

[0096] Suitably, A2 is as defined in any one of numbered paragraphs (26) to (29). Most suitably, A2 is as defined in numbered paragraph (26).

[0097] Suitably, A3 is as defined in any one of numbered paragraphs (30) to (33). Most suitably, A3 is as defined in numbered paragraph (30).

[0098] Suitably, A4 is as defined in any one of numbered paragraphs (34) to (37). Most suitably, A4 is as defined in numbered paragraph (34).

[0099] Suitably, A1, A2, A3 and A4 are as defined in any one of numbered paragraphs (38) to (45). More suitably, A1, A2, A3 and A4 are as defined in any one of numbered paragraphs (40) to (45). Most suitably, A1, A2, A3 and A4 are as defined in numbered paragraph (42).

[0100] Suitably, A2 is as defined in any one of numbered paragraphs (26) to (29). Most suitably, A2 is as defined in numbered paragraph (26).

[0101] Suitably, A3 is as defined in any one of numbered paragraphs (30) to (33). Most suitably, A3 is as defined in numbered paragraph (30).

[0102] Suitably, A4 is as defined in any one of numbered paragraphs (34) to (37). Most suitably, A4 is as defined in numbered paragraph (34).

[0103] Appropriately, R 11 is as defined in any one of the above numbered paragraphs (46) to (56). More appropriately, R 11 is as defined in any one of the above numbered paragraphs (50) to (56). Most suitably, R 11 is as defined in the numbered paragraphs (53), (54), (55) or (56) above.

[0104] Appropriately, R 12is as defined in any one of the above numbered paragraphs (57) to (61). More appropriately, R 12 is as defined in any one of the above numbered paragraphs (59) to (61). Most suitably, R 12 is as defined in the numbered paragraphs (60) or (61) above.

[0105] Appropriately, R 13 is as defined in any one of the above numbered paragraphs (62) to (64). More appropriately, R 13 is as defined in numbered paragraph (63) or (64) above. Most appropriately, R 13 is as defined in numbered paragraph (64) above.

[0106] Appropriately, R 14 is as defined in any one of the above numbered paragraphs (65) to (68). More appropriately, R 14 is as defined in the above numbered paragraphs (66), (67) or (68). Most suitably, R 14 is as defined in the numbered paragraph (68) above.

[0107] Appropriately, R a is as defined in any one of the above numbered paragraphs (69) to (73). More appropriately, R a is as defined in any one of the above numbered paragraphs (70) to (73). Most suitably, R a is as defined in the numbered paragraphs (71), (72) or (73) above.

[0108] Appropriately, R a is as defined in any one of the above numbered paragraphs (121) to (125). More appropriately, R ais as defined in any one of the above numbered paragraphs (122) to (125). Most suitably, R a is as defined in the above numbered paragraphs (123), (124) or (125).

[0109] Suitably, L is as defined in any one of the above numbered paragraphs (74) to (105). More suitably, L is as defined in any one of the above numbered paragraphs (101) to (105). Most suitably, L is as defined in the above numbered paragraphs (101), (103) or (105).

[0110] Suitably, Q is as defined in any one of the above numbered paragraphs (106) to (109). More suitably, Q is as defined in any one of the above numbered paragraphs (107) to (109). Most suitably, Q is as defined in the above numbered paragraph (107).

[0111] Suitably, X is as defined in any one of the above numbered paragraphs (110) to (115). More suitably, X is as defined in any one of the above numbered paragraphs (113) to (115). Most suitably, X is as defined in the above numbered paragraph (114).

[0112] Appropriately, L X is as defined in any one of the above numbered paragraphs (116) to (120). More appropriately, L X is as defined in any one of the above numbered paragraphs (118) to (120). Most suitably, L X is as defined in the numbered paragraph (118) above.

[0113] In one particular group of compounds of the invention, the compounds have formula II (which is a subdefinition of formula I): [ka] [In the formula, R 6 , Y1, Y2, A1, A2, A3, A4 and any related subgroups are as defined in any of the numbered paragraphs appearing herein or above], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0114] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (5) to (14) above; Y1 is -CH2- or -C(=O)-; Y2 is -CH2-, -C(=O)-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, cyano, methyl, methoxy, CF, -OCF or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1 is N, CH or CR 11 Selected from; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; provided that only one or two of A1, A2, A3 or A4 may be N; R 11 is as defined in any one of the numbered paragraphs (46) to (56) above; R 12 is as defined in any one of the numbered paragraphs (57) to (61) above; R 13 is as defined in any one of the numbered paragraphs (62) to (64) above; R 14 is as defined in any one of the numbered paragraphs (65) to (68) above.

[0115] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (5) to (14) above; Y1 is -CH2- or -C(=O)-; Y2 is as defined in any one of numbered paragraphs (17) to (22) above; A1, A2, A3 and A4 are as defined in any one of paragraphs (39) to (45) above; R 11 is as defined in any one of the numbered paragraphs (46) to (56) above; R 12 is as defined in any one of the numbered paragraphs (57) to (61) above; R 13 is as defined in any one of the numbered paragraphs (62) to (64) above; R 14 is as defined in any one of the numbered paragraphs (65) to (68) above.

[0116] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (12) to (14) above; Y1 is as defined in numbered paragraph (15) above; Y2 is as defined in any one of numbered paragraphs (18) or (19) above; A1, A2, A3 and A4 are as defined in any one of paragraphs (39) to (45) above; R 11 is as defined in any one of the numbered paragraphs (50) to (56) above; R 12 is as defined in any one of the numbered paragraphs (59) to (61) above; R 13 is as defined in any one of the numbered paragraphs (63) to (64) above; R 14 is as defined in any one of the numbered paragraphs (66) to (68) above.

[0117] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (12) above; Y1 is as defined in numbered paragraph (15) above; Y2 is as defined above in numbered paragraph (18); A1, A2, A3 and A4 are as defined in paragraph (39) above; R 11 is as defined in numbered paragraph (49) above; R 12 is as defined in numbered paragraph (59) above; R 13 is as defined in numbered paragraph (63) above; R 14is as defined in numbered paragraph (66) above.

[0118] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (13) above; Y1 is as defined in numbered paragraph (15) above; Y2 is as defined in numbered paragraph (19) above; A1, A2, A3 and A4 are as defined in paragraph (40) above; R 11 is as defined in numbered paragraph (50) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (67) above.

[0119] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (13) above; Y1 is as defined in numbered paragraph (15) above; Y2 is as defined above in numbered paragraph (20); A1, A2, A3 and A4 are as defined in paragraph (41) above; R 11 is as defined in numbered paragraph (55) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (66) above.

[0120] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (14) above; Y1 is as defined in numbered paragraph (15) above; Y2 is as defined above in numbered paragraph (20); A1, A2, A3 and A4 are as defined in paragraph (41) above; R 11 is as defined in numbered paragraph (55) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (66) above.

[0121] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (14) above; Y1 is as defined in numbered paragraph (15) above; Y2 is as defined above in numbered paragraph (21); A1, A2, A3 and A4 are as defined in paragraph (42) above; R 11is as defined in numbered paragraph (56) above; R 13 is as defined in numbered paragraph (64) above.

[0122] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y1, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 is as defined above, except that R 12 or R 13 One of: -LQ or -L x is an -X group, L is a linker; L x is a linker; X is a functional group; Q is a detection moiety.

[0123] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y1, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 is as defined above, except that R 12 or R 13 One of: -LQ group L is a linker as defined in any one of numbered paragraphs (74) to (105) above; Q is a detection moiety as defined in any one of numbered paragraphs (106) through (109) above.

[0124] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6, Y1, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 is as defined above, except that R 12 or R 13 One of: -LQ group L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; Q is a detection moiety as defined in numbered paragraph (107) above.

[0125] In one particular group of compounds of the invention, the compounds have formula I-II (which are subdefinitions of formula I): [ka] [In the formula, R 6 , Y2, A1, A2, A3, A4, and any related subgroups are as defined in any of the numbered paragraphs appearing herein or above], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0126] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (5) to (14) above; Y2 is -CH2-, -C(=O)-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, cyano, methyl, methoxy, CF, -OCF or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1 is N, CH or CR11 Selected from; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; A4 is N, CH or CR 14 Selected from; provided that only one or two of A1, A2, A3 or A4 may be N; R 11 is as defined in any one of the numbered paragraphs (46) to (56) above; R 12 is as defined in any one of the numbered paragraphs (57) to (61) above; R 13 is as defined in any one of the numbered paragraphs (62) to (64) above; R 14 is as defined in any one of the numbered paragraphs (65) to (68) above.

[0127] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (5) to (14) above; Y2 is as defined in any one of numbered paragraphs (17) to (22) above; A1, A2, A3 and A4 are as defined in any one of paragraphs (39) to (45) above; R 11 is as defined in any one of the numbered paragraphs (46) to (56) above; R 12 is as defined in any one of the numbered paragraphs (57) to (61) above; R 13is as defined in any one of the numbered paragraphs (62) to (64) above; R 14 is as defined in any one of the numbered paragraphs (65) to (68) above.

[0128] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (12) to (14) above; Y2 is as defined in any one of numbered paragraphs (18) or (19) above; A1, A2, A3 and A4 are as defined in any one of paragraphs (39) to (45) above; R 11 is as defined in any one of the numbered paragraphs (50) to (56) above; R 12 is as defined in any one of the numbered paragraphs (59) to (61) above; R 13 is as defined in any one of the numbered paragraphs (63) to (64) above; R 14 is as defined in any one of the numbered paragraphs (66) to (68) above.

[0129] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (12) above; Y2 is as defined above in numbered paragraph (18); A1, A2, A3 and A4 are as defined in paragraph (39) above; R 11is as defined in numbered paragraph (49) above; R 12 is as defined in numbered paragraph (59) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (66) above.

[0130] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (13) above; Y2 is as defined in numbered paragraph (19) above; A1, A2, A3 and A4 are as defined in paragraph (40) above; R 11 is as defined in numbered paragraph (50) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (67) above.

[0131] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (13) above; Y2 is as defined above in numbered paragraph (20); A1, A2, A3 and A4 are as defined in paragraph (41) above; R 11is as defined in numbered paragraph (55) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (66) above.

[0132] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (14) above; Y2 is as defined above in numbered paragraph (20); A1, A2, A3 and A4 are as defined in paragraph (41) above; R 11 is as defined in numbered paragraph (55) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above; R 14 is as defined in numbered paragraph (66) above.

[0133] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (14) above; Y2 is as defined above in numbered paragraph (21); A1, A2, A3 and A4 are as defined in paragraph (42) above; R 11is as defined in numbered paragraph (56) above; R 13 is as defined in numbered paragraph (64) above.

[0134] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 is as defined above, except that R 12 or R 13 One of: -LQ or -L x is an -X group, L is a linker; L x is a linker; X is a functional group; Q is a detection moiety.

[0135] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 is as defined above, except that R 12 or R 13 One of: -LQ group L is a linker as defined in any one of numbered paragraphs (74) to (105) above; Q is a detection moiety as defined in any one of numbered paragraphs (106) through (109) above.

[0136] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 is as defined above, except that R 12 or R 13 One of: -LQ group L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; Q is a detection moiety as defined in numbered paragraph (107) above.

[0137] In one particular group of compounds of the invention, the compounds have formula I-III (which are subdefinitions of formula I): [ka] [In the formula, R 6 , Y2, A1, A2, A3, A4, and any related subgroups are as defined in any of the numbered paragraphs appearing herein or above], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0138] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (5) to (14) above; Y2 is -CH2-, -C(=O)-, -CHR y2a -, -CH2-CH2-, -CH2-CHR y2b -, or -CHR y2a -CH2-; R y2a is selected from halo, cyano, methyl, methoxy, CF, -OCF or hydroxymethyl; R y2b is selected from halo, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl; A1 is N, CH or CR11 Selected from; A2 is N, CH or CR 12 Selected from; A3 is N, CH or CR 13 Selected from; provided that only one of A1, A2 and A3 may be N; R 11 is as defined in any one of the numbered paragraphs (46) to (56) above; R 12 is as defined in any one of the numbered paragraphs (57) to (61) above; R 13 is as defined in any one of the numbered paragraphs (62) to (64) above.

[0139] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in any one of the numbered paragraphs (5) to (14) above; Y2 is as defined in any one of numbered paragraphs (17) to (22) above; A1, A2 and A3 are as defined in any one of paragraphs (39) to (45) above; R 11 is as defined in any one of the numbered paragraphs (46) to (56) above; R 12 is as defined in any one of the numbered paragraphs (57) to (61) above; R 13 is as defined in any one of the numbered paragraphs (62) to (64) above.

[0140] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6is as defined in any one of the numbered paragraphs (12) to (14) above; Y2 is as defined in any one of numbered paragraphs (18) or (19) above; A1, A2 and A3 are as defined in any one of paragraphs (39) to (45) above; R 11 is as defined in any one of the numbered paragraphs (50) to (56) above; R 12 is as defined in any one of the numbered paragraphs (59) to (61) above; R 13 is as defined in any one of the numbered paragraphs (63) to (64) above.

[0141] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (12) above; Y2 is as defined above in numbered paragraph (18); A1, A2 and A3 are as defined in paragraph (39) above; R 11 is as defined in numbered paragraph (49) above; R 12 is as defined in numbered paragraph (59) above; R 13 is as defined in numbered paragraph (63) above.

[0142] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (13) above; Y2 is as defined in numbered paragraph (19) above; A1, A2 and A3 are as defined above in paragraph (40); R 11 is as defined in numbered paragraph (50) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above.

[0143] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (13) above; Y2 is as defined above in numbered paragraph (20); A1, A2 and A3 are as defined in paragraph (41) above; R 11 is as defined in numbered paragraph (55) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above.

[0144] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (14) above; Y2 is as defined above in numbered paragraph (20); A1, A2 and A3 are as defined in paragraph (41) above; R 11is as defined in numbered paragraph (55) above; R 12 is as defined in numbered paragraph (60) above; R 13 is as defined in numbered paragraph (63) above.

[0145] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined in numbered paragraph (14) above; Y2 is as defined above in numbered paragraph (21); A1, A2 and A3 are as defined in paragraph (42) above; R 11 is as defined in numbered paragraph (56) above; R 13 is as defined in numbered paragraph (64) above.

[0146] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y2, A1, A2, A3, R 11 , R 12 and R 13 is as defined above, except that R 12 or R 13 One of: -LQ or -L x is an -X group, L is a linker; L x is a linker; X is a functional group; Q is a detection moiety.

[0147] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y2, A1, A2, A3, R 11 , R 12 and R 13 is as defined above, except that R 12 or R 13 One of: -LQ group L is a linker as defined in any one of numbered paragraphs (74) to (105) above; Q is a detection moiety as defined in any one of numbered paragraphs (106) through (109) above.

[0148] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 , Y2, A1, A2, A3, R 11 , R 12 and R 13 is as defined above, except that R 12 or R 13 One of: -LQ group L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; Q is a detection moiety as defined in numbered paragraph (107) above.

[0149] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 6 is as defined in paragraph (12) above.

[0150] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 6 is as defined in paragraph (13) above.

[0151] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 6 is as defined in paragraph (14) above.

[0152] In certain groups of compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (18) above.

[0153] In certain groups of compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (19) above.

[0154] In certain groups of compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (20) above.

[0155] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, Y2 is as defined in paragraph (21) above.

[0156] In certain groups of compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined above in paragraph (22).

[0157] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (50).

[0158] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (51).

[0159] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11is as defined in paragraph (52) above.

[0160] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined in paragraph (53) above.

[0161] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (54).

[0162] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined in paragraph (55) above.

[0163] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (56).

[0164] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined in paragraph (59) above.

[0165] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined above in paragraph (60).

[0166] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined above in paragraph (61).

[0167] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 13is as defined above in paragraph (63).

[0168] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined above in paragraph (64).

[0169] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 13 is as defined in paragraph (66) above.

[0170] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 13 is as defined in paragraph (67) above.

[0171] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, R 13 is as defined above in paragraph (68).

[0172] In certain groups of compounds of formula I, II, I-II or I-III as defined herein, A4 is N or CH, particularly CH.

[0173] Certain compounds of the present invention include any of the compounds exemplified in this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following: (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydro-isoquinolin-2(1H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydro-isoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-(piperazin-1-ylmethyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((methylamino)methyl)isoindolin-2-yl)methanone; 3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)oxy)cyclobutane-1-carbonitrile; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(1-(hydroxymethyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-4-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-methoxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-ethoxy-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(pyrimidin-5-ylamino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((oxazol-4-ylmethyl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((1-methyl-1H-pyrazol-4-yl)amino)isoindolin-2-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-5-methylpyridin-2(1H)-one; (2-(cyclopropylmethoxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(cyclohexylmethoxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(cyclohexylmethoxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((5,5-difluorotetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-2-yl)methyl)amino)isoindolin-2-yl)methanone; (4-((1H-pyrazol-4-yl)amino)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)isoindolin-2-yl)methanone; 1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)pyrrolidin-1-yl)ethan-1-one; (2-((4-fluorobenzyl)oxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-((3,4-difluorobenzyl)oxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-((4-methoxybenzyl)oxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((2-methoxyethyl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((1-(oxetan-3-yl)ethyl)amino)isoindolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[6-[(dimethylamino)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[7-[(dimethylamino)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(4-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(4-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)amino)isoindolin-2-yl)methanone; (4-((2-oxabicyclo[2.2.1]heptan-4-yl)amino)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(6-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(8-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-4-((2-(2,4-dihydroxy-6-(pyridin-2-ylmethoxy)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; (R)-4-((2-(2,4-dihydroxy-6-(pyridin-2-ylmethoxy)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyrrolidin-1-yl)ethan-1-one; (R)-1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyrrolidin-1-yl)ethan-1-one; (S)-1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)piperidin-1-yl)ethan-1-one; (R)-1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)piperidin-1-yl)ethan-1-one; 1-(4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)piperidin-1-yl)ethan-1-one; 5-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpiperidin-2-one; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(pyrimidin-5-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(6-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(6-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)benzamide; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)benzamide; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(cyclopentylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((1-methylpiperidin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((1-methylpyrrolidin-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((methylamino)methyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-3-yl)amino)methyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((oxetan-3-ylamino)methyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(((3-methyloxetan-3-yl)amino)methyl)isoindolin-2-yl)methanone; (4-(aminomethyl)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone hydrochloride; (2-(benzyloxy)-4,6-dihydroxyphenyl)(7-((oxetan-3-ylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(7-(((tetrahydrofuran-3-yl)amino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-N-methylisoindoline-5-carboxamide; 2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-N,N-dimethylisoindoline-5-carboxamide; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone; (4-(azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; 2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-4-carbonitrile; 1-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile; (4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; N-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)acetamide; N-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)methyl)acetamide; (2,4-dihydroxy-6-(pyridin-3-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-(pyridin-4-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-(pyridazin-3-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; 8-Amino-3,4-dihydroisoquinolin-2(1H)-yl(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; N-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)acetamide; N-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)tetrahydrofuran-3-carboxamide; t-Butyl (5-(4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamate; (5-((4-(5-aminopentyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone hydrochloride; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-3-yl)methyl)amino)isoindolin-2-yl)methanone; 3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-N,N-dimethylpyrrolidine-1-carboxamide; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpiperidin-2-one; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(7-fluoro-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(pyridin-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(pyrazin-2-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(pyridazin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-((4-methylpiperazin-1-yl)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-((4-methylpiperazin-1-yl)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((4-methylpyrimidin-5-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2,4-dihydroxy-6-((3-methylbenzyl)oxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-((dimethylamino)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-((dimethylamino)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinolin-6-yl)(4-methylpiperazin-1-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-N,N-dimethyl-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide; (S)-2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-N,N-dimethyl-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide; (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl)amino)-1-methylpyridin-2(1H)-one; 5-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyridin-2(1H)-one; 5-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyridin-2(1H)-one; (R)-4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one; (S)-4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one; (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(cyclohexylmethoxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2-(cyclopropylmethoxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(6-(2-methoxyethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(methyl(tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-(benzyloxy)-4,6-dihydroxyphenyl-(5-((oxetan-3-ylamino)methyl)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-(((tetrahydrofuran-3-yl)amino)methyl)isoindolin-2-yl)methanone; 1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)azetidin-1-yl)ethan-1-one; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((1,1-dioxidotetrahydrothiophen-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((1,1-dioxidotetrahydrothiophen-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((1,1-dioxidotetrahydrothiophen-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((4-methoxytetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 1-(3-((2-(2-(benzyloxy)-4,6-bis(methoxymethoxy)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)(methyl)amino)azetidin-1-yl)ethan-1-one; (S)-1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)(methyl)amino)pyrrolidin-1-yl)-4-methoxybutan-1-one; (S)-1-(3-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyrrolidin-1-yl)-4-methoxybutan-1-one; 5-((5-(4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate; t-Butyl (5-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)carbamate; N-(5-aminopentyl)-2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamide hydrochloride; 5-((5-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate; 1-(6-((5-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)amino)-6-oxohexyl)-3,3-dimethyl-2-((1E,3E)-5-((E)-1,3,3-trimethylindolin-2-ylidene)penta-1,3-dien-1-yl)-3H-indol-1-ium formate; N-(5-(4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)-3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propenamide; and 2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-N-(5-(3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-4λ) 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanamido)pentyl)isoindoline-5-carboxamide

[0174] The various functional groups and substituents that make up the compounds of formula (I) or sub-formulae (II) to (I-XII) are typically chosen so that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, the molecular weight of the compound is less than 900, e.g., less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, e.g., less than 550.

[0175] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic, e.g., acid-addition salts of the compounds of the present invention, e.g., acid-addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, e.g., sodium or potassium salts, alkaline earth metal salts, e.g., calcium or magnesium salts, ammonium salts, or salts with organic bases that form pharmaceutically acceptable cations, e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0176] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of one another are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates plane-polarized light and can be designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomer, respectively). Chiral compounds can exist as either enantiomer or a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0177] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds can be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include both individual enantiomers and their mixtures, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some compounds of the present invention may have geometric isomeric centers (E- and Z-isomers).

[0178] It is to be understood that the present invention embraces all optical, diastereomeric, and geometric isomers and mixtures thereof that possess activity.

[0179] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T); C can be in any isotopic form, including 12C, 13C, and 14C; O can be in any isotopic form, including 16O and 18O, etc.

[0180] It is also to be understood that some compounds of formula (I), or subformulas (II) through (I-XII), can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, etc. It is to be understood that the present invention encompasses all such solvated forms that possess activity.

[0181] It is also to be understood that some compounds of formula (I), or subformulas (II) to (I-XII), may exhibit polymorphism, and that the present invention encompasses all such forms that possess activity.

[0182] Compounds of formula (I), or sub-formulas (II) to (I-XII), can exist in many different tautomeric forms, and references to compounds of formula (I), or sub-formulas (II) to (I-XII), include all such forms. For the avoidance of doubt, compounds may exist in one of several tautomeric forms, and only one will be described or shown in detail, while all others are encompassed by formula (I), or sub-formulas (II) to (I-XII). Examples of tautomeric forms include, for example, the keto, enol, and enolate forms for the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0183] [ka]

[0184] Compounds of formula (I) or subformulas (II) to (I-XII) containing an amine functional group can also form N-oxides. References herein to compounds of formula (I) or subformulas (II) to (I-XII) containing an amine functional group also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Particular examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, the N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which the amine compounds are reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0185] The compounds of formula (I), or subformulas (II) to (I-XII), can be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at carboxy or hydroxy groups in compounds of formula (I), or subformulas (II) to (I-XII), and in vivo cleavable amide derivatives that can be formed at carboxy or amino groups in compounds of formula (I), or subformulas (II) to (I-XII).

[0186] Thus, the present invention includes compounds of formula (I), or sub-formulas (II) to (I-XII), as defined above, when available by organic synthesis and when available in the human or animal body as cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula (I), or sub-formulas (II) to (I-XII), produced by organic synthetic means, and also compounds produced in the human or animal body as metabolism of precursor compounds that are compounds of formula (I), or sub-formulas (II) to (I-XII), which may be synthetically produced compounds or metabolically produced compounds.

[0187] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or subformulas (II) to (I-XII), are those based on sound medical judgment, such that they are free from undesirable pharmacological activity and are free from undue toxicity and are suitable for administration to the human or animal body.

[0188] Various forms of prodrugs are 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”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0189] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or sub-formulas (II) to (I-XII), containing a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I, or sub-formulas (II) to (I-XII), containing a carboxy group are, for example, pharmaceutically acceptable esters which are cleaved in the human or animal body to produce the parent acid or 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 ester, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthalidyl ester, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester.

[0190] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or sub-formulas (II) to (I-XII) having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compounds of formula (I) or sub-formulas (II) to (I-XII) containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters, such as phosphate esters (including phosphoramidate cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include (1-10C)alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and (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 hydroxy groups include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl groups.

[0191] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or sub-formulae (II) to (I-XII), having a carboxy group are, for example, in vivo cleavable amides thereof, such as amides formed with amines, such as ammonia, (1-4C)alkylamines, such as methylamine, [(1-4C)alkyl]2amines, such as dimethylamine, N-ethyl-N-methylamine or diethylamine, (1-4C)alkoxy-(2-4C)alkylamines, such as 2-methoxyethylamine, phenyl-(1-4C)alkylamines, such as benzylamine and amino acids, such as glycine or its esters.

[0192] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or subformulae (II) to (I-XII), having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, amides formed with (1-10C)alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(1-4C)alkyl)piperazin-1-ylmethyl.

[0193] The in vivo effects of the compounds of formula (I), or sub-formulas (II) to (I-XII), may be exerted in part by one or more metabolic products formed in the human or animal body after administration of the compounds of formula (I), or sub-formulas (II) to (I-XII). As described below, the in vivo effects of the compounds of formula (I), or sub-formulas (II) to (I-XII), may also be exerted as a result of metabolism of precursor compounds (prodrugs).

[0194] While the invention may relate to any compound or particular group of compounds defined herein as an optional, preferred or suitable feature or otherwise in relation to certain particular embodiments, the invention may relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable feature or certain particular embodiment.

[0195] Suitably, the present invention excludes any individual compound that does not have biological activity as defined herein.

[0196] <Synthesis> The compounds of the present invention can be prepared by any suitable technique known in the art. Certain methods for the preparation of these compounds are further described in the accompanying examples.

[0197] In the descriptions of synthetic methods described herein and in any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedure, can be selected by one skilled in the art.

[0198] 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 employed.

[0199] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or of some of the starting materials, it may be desirable to protect some of the substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups can be introduced and subsequently removed.

[0200] For examples of protecting groups, see one of the many general texts on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (published by John Wiley & Sons, Inc.) Protecting groups can 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 method being chosen to effect removal of the protecting group with minimal disturbance to other groups in the molecule.

[0201] Thus, for example, if the reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0202] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl, alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example, benzyloxycarbonyl, or aroyl groups, for example, benzoyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, for example, lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups may be removed by treatment with a suitable acid, for example, hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed, for example, by hydrogenation over a catalyst, for example, 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.

[0203] Suitable protecting groups for hydroxy groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl, aroyl groups, for example, benzoyl, or arylmethyl groups, for example, benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, such as lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed, for example, by hydrogenation over a catalyst, for example, palladium on carbon.

[0204] A suitable protecting group for a carboxy group is, for example, an esterifying group, a methyl or ethyl group which may be removed, for example, by hydrolysis with a base such as, for example, sodium hydroxide, or a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or a benzyl group which may be removed, for example, by hydrogenation over a catalyst, for example palladium on carbon.

[0205] Resins can also be used as protecting groups.

[0206] The methodology used to synthesize compounds of formula (I), or subformulas (II) to (I-III), will vary depending on the nature of any substituents or associated subgroups thereof. Suitable methods for their preparation are further described in the accompanying examples.

[0207] After a compound of formula (I), or sub-formulas (II) to (I-III), has been synthesized by any one of the methods defined herein, the methods may then proceed to the following further step: (i) removing any protecting groups present; (ii) converting a compound of 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 It may further include:

[0208] An example of (ii) above is where a compound of formula (I) is synthesized and then R 2 , R 4 , R 6 , R 11 , R 12 , R 13 or R 14 This is where one or more of the groups can be further reacted to change the nature of that group, providing alternative compounds of formula (I).

[0209] The resulting compounds of formula (I), or subformulas (II) to (I-III), can be isolated and purified using techniques well known in the art.

[0210] Compounds of formula (I) can be synthesized by the synthetic routes shown in the Examples section below.

[0211] <Biological activity> The pharmacological effects of the compounds of the present invention can be determined using the biological assays described in the Examples section herein.

[0212] Although the pharmacological properties of compounds of formula (I) vary with structural variations, as expected, compounds of the present invention have been found to be active in the MLH1 in vitro assay described in the Examples section, and in some cases in the MLH1 and PMS2 in vitro assays described in the Examples section.

[0213] <Pharmaceutical Composition> According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0214] Compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0215] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0216] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0217] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain 0.5 mg to 0.5 g (more suitably, 0.5 to 100 mg, e.g., 1 to 30 mg) of active agent, combined with an appropriate and convenient amount of excipients, which may vary, for example, from about 5 to about 98 weight percent of the total composition.

[0218] The size of an administered dose of a compound of formula I for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, according to well-known principles of medicine.

[0219] When using the compounds of the present invention for therapeutic or prophylactic purposes, they are generally administered in a daily dose range, for example, 0.1 mg / kg to 75 mg / kg body weight, taking into account the need for divided doses. Generally, lower doses are administered when parenteral routes are used. Thus, for example, for intravenous or intraperitoneal administration, a dose range, for example, 0.1 mg to 30 mg / kg body weight, is generally used. Similarly, for administration by inhalation, a dose range, for example, 0.05 mg to 25 mg / kg body weight, is used. Oral administration may also be appropriate, particularly in tablet form. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of the compounds of the present invention.

[0220] Therapeutic Uses and Applications The present invention provides compounds that function as inhibitors of MLH1 activity or MLH1 and PMS2 activity.

[0221] Thus, compounds of formula (I), or pharmaceutically acceptable salts thereof, have potential therapeutic use in a variety of disease states in which inhibition of MLH1 activity, or MLH1 and PMS2 activity, is beneficial.

[0222] Accordingly, the present invention provides a method for treating a disease or disorder in which inhibition of MLH1 activity or MLH1 and PMS2 activity is beneficial in a patient in need of such treatment, said method comprising the step of 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.

[0223] The present invention provides a method for inhibiting MLH1 activity or MLH1 and PMS2 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0224] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0225] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0226] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0227] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use as a pharmaceutical.

[0228] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

[0229] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer. In a particular embodiment, the cancer is a human cancer, particularly an estrogen-positive cancer, such as breast cancer, or an androgen receptor-positive cancer, such as prostate cancer.

[0230] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting MLH1 activity or MLH1 and PMS2 activity.

[0231] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which inhibition of MLH1 activity or MLH1 and PMS2 activity is beneficial.

[0232] The invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

[0233] The present invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0234] The invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the inhibition of MLH1 activity or MLH1 and PMS2 activity.

[0235] The present invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of MLH1 activity or MLH1 and PMS2 activity is beneficial.

[0236] The terms "proliferative disorder," "proliferative condition," and "proliferative disease" are used interchangeably herein and relate to unwanted or uncontrolled cell proliferation, either in vitro or in vivo, of excessive or abnormal cells that are unwanted, e.g., neoplastic or hyperplastic growth.

[0237] In the above-outlined aspects of the invention, the proliferative disorder is suitably cancer, and the cancer is suitably human cancer. In the aspects of the invention outlined herein, the proliferative disorder is suitably cancer, and the cancer is suitably human cancer. In particular, the compounds of the invention are useful in treating any cancer in which mismatch repair inhibition and / or cGAS-STING pathway activation is beneficial.Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal 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 tumor, cervical cancer, colorectal cancer, Cowden disease, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, etc.). Chromoma, 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 carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloblastic leukemia (CRL), 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 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), cancer of the nasal cavity and paranasal sinuses, nasopharyngeal carcinoma, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis type 1 and type 2, nevoid basal cell carcinoma syndrome , oral or oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumors, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas (e.g., Kaposi or soft tissue), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, vulvar cancer, Waldenström's macroglobulinemia, Werner's syndrome, Wilms' tumor, and xeroderma pigmentosum).Particular cancers of interest include hematological cancers, such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-esophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0238] The compounds of the present invention may also be used to treat triplet diseases.

[0239] Thus, a further aspect of the present invention provides a method of treating a triplet disorder (e.g., Huntington's disease (HD), myotonic dystrophy type 1 (DM1), Fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar degeneration (SCAs)) in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0240] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in treating a triplet disorder. In particular embodiments, the triplet 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 degeneration (SCAs).

[0241] According to a further aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a triplet disorder. In particular embodiments, the triplet 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 degeneration (SCAs).

[0242] <Administration route> The compounds of the invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic, peripheral, or local (i.e., at the desired site of action).

[0243] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., patches, plasters, etc.); transmucosally (including, e.g., patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via aerosol, e.g., through the mouth or nose, using); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); by injection, including, e.g., intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intraarticular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; parenterally, e.g., by a depot or reservoir placement, subcutaneously or intramuscularly.

[0244] <Combination therapy> The compounds of the present invention can be administered as a monotherapy, or the compounds of the present invention can be used in addition to conventional surgery or radiation therapy or chemotherapy or targeted agents. Such chemotherapy or targeted agents can include one or more of the following categories: (i) As used in medical oncology, antiproliferative / antineoplastic agents and combinations thereof, for example, but not limited to, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea). antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); (ii) Cytostatic agents, such as, but not limited to, antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprolide, and buserelin), progestogens (e.g., megestrol acetate), and corticosteroids (e.g., dexamethasone, prednisone, and prednisolone), steroid hormones, including aromatase inhibitors (such as anastrozole, letrozole, vorazole, and exemestane), and inhibitors of 5α-reductase, such as finasteride; (iii) anti-invasion agents, such as, but not limited to, the c-Src kinase family inhibitor 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application Publication No. 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-type plasminogen activator receptor function or antibodies against heparanase; (iv) inhibitors of growth factor function, including, but not limited to, growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and the antibody described by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, and any growth factor or growth factor receptor antibody disclosed by I. M. Schmidt, M ... inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib (BAY43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling via MEK and / or AKT kinase, 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, including, but not limited to, those that inhibit the effects of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), and pazopanib (GW786034)]. (vi) vascular damaging agents, such as, but not limited to, combretastatin A4 and compounds disclosed in International Patent Application Publications WO99 / 02166, WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; (viii) antisense therapy, including but not limited to those directed to the targets set forth above, e.g., ISIS2503, anti-ras antisense, etc.; (ix) Immunotherapeutic approaches, including, for example, cancer vaccines, antibodies, viruses (oncolytic viruses), and small molecule or cell therapy approaches to increase the immunogenicity of a patient's tumor cells and / or facilitate a cell-mediated anti-tumor response. Such therapies may include, but are not limited to, OX40 agonists, cGAS-STING agonists, A2a receptor antagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, arginase inhibitors, BTK inhibitors, and bromodomain inhibitors; transduction of cancer antigens using microbial vectors; direct transduction of cancer antigens into antigen-presenting cells; treatment with cancer antigen-specific immune cells (e.g., CAR-T); treatment with antibodies, antibody fragments, and antibody-drug conjugates that enable the immune system to recognize tumor cells.

[0245] Such conjoint treatment may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the dosage ranges described hereinabove and the other pharmaceutically active agent(s) within their approved dosage ranges.

[0246] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (e.g. cancer involving a solid tumour) comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and an anti-tumour agent.

[0247] According to this aspect of the invention, there is provided a combination for use in the treatment of a proliferative condition, such as cancer (e.g., a cancer involving a solid tumor), comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and any one of the anti-tumor agents set out in the specification above.

[0248] In a further aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer, optionally in combination with another anti-tumour agent selected from those set out in the specification above.

[0249] In a further aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer, optionally in combination with a tyrosine kinase inhibitor, optionally selected from those set out in the specification above.

[0250] When the term "combination" is used herein, it is understood to mean simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" means simultaneous administration. In another aspect of the present invention, "combination" means separate administration. In a further aspect of the present invention, "combination" means sequential administration. When administration is sequential or separate, the delay in administering the second component should not, for example, cause the beneficial effect of the combination to be lost.

[0251] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anti-tumour agent (optionally selected from those set out in the specification above), together with a pharmaceutically acceptable diluent or carrier.

[0252] <Combination therapy with immunomodulation therapy> Immune checkpoint inhibitors Immune checkpoint proteins present in 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-tumor immune responses. Inhibitors of these immune checkpoint proteins (e.g., CTLA4, LAG3, PD1, PD-L1, TIM-3, and / or TIGIT inhibitors) promote anti-tumor immune responses that can be used to effectively treat some forms of cancer.

[0253] immunostimulants Monoclonal antibodies, bispecific antibodies, recombinant ligands, and small molecule therapeutics that bind to stimulatory receptors on immune cells can facilitate effective anti-tumor responses. Such receptors may be involved in cell-to-cell contact, for example, contact between tumor cells and immune cells or contact between two types of immune cells, while other receptors may bind to soluble factors that stimulate an immune response. In one such embodiment, antibodies, bispecific antibodies, recombinant proteins, or small molecule therapeutics can activate stimulatory receptors, including, but not limited to, 4-1BB, OX40, cGAS-STING, CD27, CD40, and DR3, which enhance anti-tumor immunity.

[0254] A modulator of antigen processing can facilitate the presentation of neoantigenic peptides on the cell surface to enhance effective antitumor responses. In one such embodiment, an inhibitor of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 can stimulate antitumor immunity.

[0255] In one aspect, the invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0256] In another aspect, the invention relates to the use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

[0257] In another aspect, the present invention relates to a method of treating a proliferative disorder in a subject in need thereof, comprising the step of administering to said subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein.

[0258] In another aspect, the 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 pharmaceutically acceptable salt thereof is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or an immunostimulant, or a pharmaceutically acceptable salt thereof.

[0259] In another aspect, the present invention relates to an immune checkpoint inhibitor or immunostimulant, 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 administration with a compound defined herein, or a pharmaceutically acceptable salt thereof.

[0260] In another aspect, the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor or immunostimulant, or a pharmaceutically acceptable salt thereof.

[0261] In another aspect, the invention relates to the use of an immune checkpoint inhibitor or immunostimulant, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with a compound defined herein, or a pharmaceutically acceptable salt thereof.

[0262] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising the step of sequentially, separately or simultaneously administering therapeutically effective amounts of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0263] Any immune checkpoint inhibitor or immunostimulatory agent can be used in the combination therapy defined herein.

[0264] In one aspect, the immune stimulator is selected from a 4-1BB stimulator, an OX40 stimulator, a CD27 stimulator, a CD40 stimulator, and a DR3 stimulator. In another embodiment, the immune checkpoint inhibitor is selected from a PD1 inhibitor, a PD-L1 inhibitor, a LAG3 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, and / or a TIGIT inhibitor. In a detailed embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[0265] PD-1 is a cell surface receptor protein present on immune cells, such as T cells. PD-1 plays an important role in promoting self-tolerance by downregulating the immune system and suppressing T cell activation. PD-1 protein is an immune checkpoint that monitors autoimmunity through a dual mechanism: it promotes apoptosis (programmed cell death) of antigen-specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressor T cells).

[0266] PD-1 therefore suppresses the immune system, which prevents autoimmune diseases but can also prevent the immune system from killing cancer cells.

[0267] PD1 binds to two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest because it is highly expressed in several cancers, and its role in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 to boost the immune system have been approved or are being developed for the treatment of cancer. Many tumor cells express PD-L1, the immunosuppressive PD-1 ligand; inhibiting the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate pro-oncogenic antitumor activity. This is known as immune checkpoint blockade.

[0268] 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, renal cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. They are also being investigated 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).

[0269] Examples of drugs that block PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). These drugs have also been shown to help treat 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 in other types of cancer.

[0270] Examples of LAG3 inhibitors include BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (a bispecific DART combining PD-1 and LAG-3), GSK2831781, and LAG525.

[0271] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab.

[0272] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Lilly).

[0273] 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).

[0274] In one aspect, 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.

[0275] <Combination Therapy with DNA Damage Response Modulators>

[0276] The compounds of the present invention are particularly suitable for use in combination with agents that act as DNA damage response modulators, such as PARP inhibitors, ATM inhibitors, and ATR inhibitors.

[0277] In one aspect, the 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.

[0278] In another aspect, the invention relates to the 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 a proliferative disorder.

[0279] In another aspect, the present invention relates to a method of treating a proliferative disorder in a subject in need thereof, comprising the step of 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.

[0280] 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 administered simultaneously, separately or sequentially 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.

[0281] In another aspect, the invention relates to the 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 administration 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.

[0282] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising the step of sequentially, separately or simultaneously administering to a subject in need thereof a therapeutically effective amount of a compound 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.

[0283] Any DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) can be used in the combination therapies defined herein.

[0284] <Combination Therapy with DNA Damage Response Modulators> The compounds of the present invention are particularly suitable for use in combination with agents that act as DNA damage response modulators, such as PARP inhibitors, ATM inhibitors and ATR inhibitors.

[0285] In one aspect, the present invention relates to a combination comprising a compound 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.

[0286] In another aspect, the present invention relates to the use of a combination comprising a compound 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 a proliferative disorder.

[0287] In another aspect, the present invention relates to a method of treating a proliferative disorder in a subject in need thereof, comprising the step of 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.

[0288] 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 pharmaceutically acceptable salt thereof is for simultaneous, separate or sequential administration 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.

[0289] In another aspect, the invention relates to the 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 administration 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.

[0290] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising the step of sequentially, separately or simultaneously administering to a subject in need thereof therapeutically effective amounts 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.

[0291] Any DNA damage response modulator (eg, a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) can be used in the combination therapy defined herein.

[0292] <Probe Compound of the Present Invention> In another aspect, the present invention provides a compound comprising R 12 or R 13 is -LQ or -L as defined herein x The present invention provides a probe compound of formula I, II, I-II, I-III, or a salt thereof, as defined herein, wherein -X is a group.

[0293] The probe compounds of the present invention are selective for MLH1 or MLH1 and PMS2, depending on the nature of the compound of formula I.

[0294] The linker group L may be any suitable linker moiety that attaches the detection moiety Q to the remainder of the probe compound of Formula I, II or I-III as defined herein.

[0295] Suitably, the linker group L is 3 to 30 atoms in length, more suitably 4 to 20 atoms in length, and even more suitably 5 to 18 atoms in length. In particular groups of probe compounds of formula I or II as defined herein, L is 5 to 12 atoms in length.

[0296] Suitably, L is as defined in any one of paragraphs (74) to (105) above. More suitably, L is as defined in any one of paragraphs (101), (103) or (105) above. In certain groups of probe compounds of formula I or II, L is as defined in paragraph (103) or (105) above.

[0297] The detection moiety Q can be any moiety that can detect and quantify a probe compound of Formula I. As described further below, the probe compounds of Formula I, as defined herein, are designed for use in displacement assays, whereby the ability of a test compound to displace a probe compound of Formula I from the ATP-binding site of a target protein (e.g., MLH1 or PMS2) can be used to determine the binding affinity of the test compound for the ATP-binding site of the target protein. Thus, the detection moiety Q can be any moiety that can be easily detected and quantified. In certain circumstances, the detection moiety Q is capable of detecting and quantifying any probe compound of Formula I that has been displaced (i.e., "unbound") from the ATP-binding site of the target protein. In some embodiments of the present invention, this can be achieved by collecting any displaced or "unbound" compound of Formula I from a test sample and assaying the sample to determine how much unbound probe compound is present. This, in turn, provides an indication of how much of the probe compound present in the sample has been displaced by the test compound.

[0298] It will therefore be understood that the nature of the detection moiety Q is not critical, so long as it can be used to determine the amount of probe compound of formula I present in a sample. Those skilled in the art will be able to select an appropriate detection moiety Q and an appropriate methodology for detecting and quantifying the amount of compound of formula I in a sample, in particular for detecting the amount of probe compound of formula I that has been displaced from the ATP-binding site of a target protein by a test compound.

[0299] Suitably, the detection moiety Q is selected from the group consisting of a fluorophore, an oligonucleotide, a biomolecule, a molecular sensor, a protein, or a peptide.

[0300] In embodiments in which the detection moiety Q is an oligonucleotide, biomolecule, molecular sensor, protein, or peptide, any suitable technique known in the art for detecting and quantifying the amount of oligonucleotide, biomolecule, molecular sensor, protein, or peptide present can be utilized. For example, a fluorescently labeled secondary probe can be used that can specifically bind to the detection moiety Q of a probe compound of Formula I, and after any excess secondary probe is removed, the amount of binding of the secondary probe to the detection moiety Q of the compound of Formula I can be detected and quantified, thereby allowing the amount of the probe compound of Formula I to be determined.

[0301] For example, when Q is an oligonucleotide, a secondary probe having a suitable detectable label, e.g., a fluorophore or radiolabel, and a complementary oligonucleotide sequence capable of hybridizing to Q can be used to detect and quantify the amount of the probe compound of Formula I present in a sample (suitably the amount of probe compound displaced from the ATP binding site of the target protein by the test compound). Similarly, when Q is a protein or peptide, the secondary probe can be an antibody capable of selectively binding to the protein or peptide and a suitable detectable label, e.g., a fluorophore or radiolabel.

[0302] More suitably, the detection moiety Q is a fluorophore. In such cases, the compound of formula I can be used in a fluorescence polarization assay. In a particular group of probe compounds of formula I, the detection moiety Q is a fluorophore selected from the group consisting of AlexaFluor dyes, cyanine dyes, fluorescein, BODIPY or BODIPY derivatives (e.g., BODIPY TMR), TAMRA, Oregon Green dyes, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red. In a further group of probe compounds of formula I, the detection moiety Q is a fluorophore selected from the group consisting of AlexaFluor-647, AlexaFluor-633, AlexaFluor-594, AlexaFluor-488, cyanine-5B, cyanine-3B, fluorescein, BODIPY TMR, TAMRA, Oregon Green 488, Oregon Green 514, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red.

[0303] Suitably, Q is as defined in any one of numbered paragraphs (106) to (109) above. More suitably, Q is as defined in any one of numbered paragraphs (107) to (109) above. Most suitably, Q is as defined in numbered paragraph (107) above.

[0304] It is understood that X may be any suitable functional group that is capable of reacting with a detection moiety, Q, as defined herein, or a functional group present in a compound of formula Q-L2-Y, to covalently attach the detection moiety to a compound of formula II, thereby forming a compound of formula I, as defined herein.

[0305] Those skilled in the art will be familiar with suitable functional groups that can be used to form a covalent bond with an appropriate detection moiety. For example, X can be halo, N3, or ethynyl ( [ka] ) can be selected.

[0306] In particular embodiments, X is N3 or ethynyl.

[0307] Suitably, X is a functional group capable of reacting with a functional group present in the detection moiety to form a bond or a triazole bond between the detection moiety and the compound of formula I, II. In particular embodiments, the bond formed is a triazole bond (which may be formed by click chemistry).

[0308] Suitably, X is as defined in any one of numbered paragraphs (110) to (115) above. More suitably, X is as defined in any one of numbered paragraphs (113) to (115) above. Most suitably, X is as defined in numbered paragraph (114) above.

[0309] In certain embodiments of the present invention, R 12 or R 13 Compounds of formula I, II, I-II or I-III in which one of R is a -LQ group are 12 or R 13 One of them is -L x -X group to a compound of formula I with the formula: QL y -Y [In the formula, Q is the detection moiety defined above: L y is absent or is L of the compound of formula II x is a linker group that, when covalently attached to the group, forms the linker L of the compound of formula I, II, I-II, or I-III; Y reacts with the functional group X present in the compound of formula II to convert Q-L2 to L of the compound of formula I, II, I-II or I-III. x is a functional group capable of covalently bonding to form a -LQ group.

[0310] In one embodiment, L y is a (1-8C) alkylene linker, the alkylene chain being provided with one or more -O-, -C(O)NR located within the alkylene chain and / or at one of its termini; q1 -, -NR q1 optionally further comprising a C(O)-, -C(O)O-, -OC(O)- or triazole ring bond; R q1 is hydrogen or (1-2C) alkyl.

[0311] In another embodiment, L y is a (1-8C) alkylene linker, the alkylene chain having one -O-, -C(O)NR located within the alkylene chain and / or at one of its termini; q1 -, -NR q1 optionally further comprising a C(O)-, -C(O)O-, -OC(O)- or triazole ring bond; R q1 is hydrogen or (1-2C) alkyl.

[0312] In a further embodiment, L y is a (1-5C) alkylene linker.

[0313] In another embodiment, L y is a (1-3C) alkylene linker.

[0314] Y reacts with the functional group X present in the probe compound of formula II to form QL y It is understood that the group can be any suitable functional group capable of covalently attaching to a compound of formula II, thereby forming a compound of formula I as defined herein.

[0315] Those skilled in the art are familiar with suitable functional groups that can be used to form a covalent bond with functional group X in a compound of Formula I, II, I-II, or I-III. For example, Y can be selected from halo, N, or ethynyl.

[0316] In particular embodiments, when X is ethynyl, Y is N3, or when X is N3, Y is ethynyl.

[0317] Suitably, Y is a functional group capable of reacting with a functional group X present in a probe compound of formula I, II, I-II or I-III to form a bond or a triazole bond. In particular embodiments, the bond formed is a triazole bond (which may be formed by click chemistry).

[0318] Linker group L x may be any suitable linker moiety that attaches the functional group X to the remainder of the probe compound of formula I, II, I-II or I-III as defined herein. x is as defined in any one of the numbered paragraphs (116) to (120) above. More appropriately, L x is as defined in any one of the numbered paragraphs (118) to (120) above. Most appropriately, L x is as defined above in numbered paragraph (118).

[0319] In one particular group of probe compounds of the present invention, the probe compound has formula I, 2 , R 4 , R 6 , Y1, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 each have one of the definitions set forth above, except that R 12 or R 13 One of: -LQ group L is a linker; and Q is a detection moiety.

[0320] Suitably, in the probe compound of formula I, L is a linker as defined in any one of numbered paragraphs (74) to (105) above; and Q is a detection moiety as defined in any one of numbered paragraphs (106) to (109) above. More suitably, L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; and Q is a detection moiety as defined in numbered paragraph (107) above.

[0321] In another group of probe compounds of the present invention, the compound has formula II shown above, where R 6 , Y1, Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R 14 each have one of the definitions set forth above, except that R 12 or R 13 One of: -LQ group L is a linker and Q is a detection moiety; or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0322] Suitably, in the probe compound of formula II, L is a linker as defined in any one of numbered paragraphs (74) to (105) above; and Q is a detection moiety as defined in any one of numbered paragraphs (106) to (109) above. More suitably, L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; and Q is a detection moiety as defined in numbered paragraph (107) above.

[0323] In another group of probe compounds of the present invention, the compound has Formula I-II shown above, where R 6 , Y2, A1, A2, A3, A4, R 11 , R 12 , R 13 and R14 each have one of the definitions set forth above, except that R 12 or R 13 One of: -LQ group L is a linker and Q is a detection moiety; or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0324] Suitably, in the probe compounds of formula I-II, L is a linker as defined in any one of numbered paragraphs (74) to (105) above; and Q is a detection moiety as defined in any one of numbered paragraphs (106) to (109) above. More suitably, L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; and Q is a detection moiety as defined in numbered paragraph (107) above.

[0325] In another group of probe compounds of the present invention, the compounds are those of Formulas I-III shown above, where R 6 , Y2, A1, A2, A3, R 11 , R 12 and R 13 each have one of the definitions set forth above, except that R 12 or R 13 One of: -LQ group L is a linker and Q is a detection moiety; or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0326] Suitably, in the probe compounds of formulas I-III, L is a linker as defined in any one of numbered paragraphs (74) to (105) above; and Q is a detection moiety as defined in any one of numbered paragraphs (106) to (109) above. More suitably, L is a linker as defined in any one of numbered paragraphs (101), (103), or (105) above; and Q is a detection moiety as defined in numbered paragraph (107) above.

[0327] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 6 is as defined in paragraph (12) above.

[0328] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 6 is as defined in paragraph (13) above.

[0329] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 6 is as defined in paragraph (14) above.

[0330] In certain groups of probe compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (18) above.

[0331] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, Y2 is as defined in paragraph (19) above.

[0332] In certain groups of probe compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (20) above.

[0333] In certain groups of probe compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (21) above.

[0334] In certain groups of probe compounds of formula I, II, I-II or I-III defined herein, Y2 is as defined in paragraph (22) above.

[0335] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (50).

[0336] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (51).

[0337] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined in paragraph (52) above.

[0338] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined in paragraph (53) above.

[0339] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (54).

[0340] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined in paragraph (55) above.

[0341] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 11 is as defined above in paragraph (56).

[0342] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined in paragraph (59) above.

[0343] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined above in paragraph (60).

[0344] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined above in paragraph (61).

[0345] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 13 is as defined above in paragraph (63).

[0346] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 12 is as defined above in paragraph (64).

[0347] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 13 is as defined in paragraph (66) above.

[0348] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 13is as defined in paragraph (67) above.

[0349] In certain groups of probe compounds of formula I, II, I-II or I-III as defined herein, R 13 is as defined above in paragraph (68).

[0350] In one particular group of probe compounds of formula I, II, I-II or I-III as defined herein, A4 is N or CH, particularly CH.

[0351] Certain probe compounds of the present invention include any of the compounds exemplified in this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following: 5-((5-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate; 1-(6-((5-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)amino)-6-oxohexyl)-3,3-dimethyl-2-((1E,3E)-5-((E)-1,3,3-trimethylindolin-2-ylidene)penta-1,3-dien-1-yl)-3H-indol-1-ium formate; N-(5-(4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)-3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-4λ 4 ,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propenamide; and 2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-N-(5-(3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-4λ) 4,5λ 4 -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanamido)pentyl)isoindoline-5-carboxamide 5-((5-(4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate t-Butyl (5-(2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)carbamate N-(5-aminopentyl)-2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamide hydrochloride

[0352] Suitable salts of the probe compounds of the present invention are, for example, acid-addition salts of the compounds of the present invention that are sufficiently basic, for example, with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases.

[0353] The present invention also encompasses probe compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3 H(T) can be in any isotopic form; C can be 12 C. 13 C and 14 It can be in any isotopic form, including C; O is 16 O and 18 It can be in any isotopic form, including O; and the like.

[0354] It is also to be understood that some of the probe compounds of formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms.

[0355] It is also to be understood that some probe compounds of formula (I) may exhibit polymorphism, and that the present invention encompasses all such polymorphic forms.

[0356] Some probe compounds of formula (I) may also exist in a number of different tautomeric forms, and references to compounds of formula (I) include all such forms.

[0357] <Synthesis of probe compounds> In another aspect, the present invention provides a method of synthesizing a probe compound of Formula I, II or I-III, or a salt thereof, as defined herein.

[0358] The probe compounds of the present invention can be prepared by any suitable technique known in the art. Certain methods for the preparation of these compounds are further described in the accompanying examples.

[0359] In the descriptions of synthetic methods described herein and in any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedure, can be selected by one skilled in the art.

[0360] 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 employed.

[0361] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or of some of the starting materials, it may be desirable to protect some of the substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups can be introduced and subsequently removed.

[0362] For the example of protecting groups, see one of the many general texts on the subject, e.g., 'Protective Groups in Organic Synthesis' by Theodora Green; th Edition; 2006 (Publisher: John Wiley & Sons, Inc.) Protecting groups can 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 method being chosen to effect removal of the protecting group with minimal disturbance to other groups in the molecule.

[0363] In one aspect, the present invention provides a method for synthesizing a compound of formula I as defined herein, the method comprising: reacting R 12 or R 13 -L as defined herein x reacting a compound of formula I, II, I-II or I-III, which is a -X group, with a compound of formula Q-L2-Y as defined herein; and optionally thereafter: (i) removing any protecting groups present; (ii) forming a salt of a compound of formula I; and / or (iii) isolating and purifying the compound of formula I, II, I-II, or I-III. Includes.

[0364] <Applications of probe compounds> In one aspect, the present invention provides the use of a probe compound of Formula I, II, I-II or I-III, or a salt thereof, as defined herein, in a displacement assay to determine the binding affinity of a test molecule to the ATP-binding site of a target protein.

[0365] In another aspect, the present invention provides a probe compound of Formula I, II, I-II or I-III, or a salt thereof, for use in a displacement assay for determining the binding affinity of a test molecule to the ATP-binding site of a target protein.

[0366] In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a particular embodiment, the target protein is MLH1 and PMS2. In a particular embodiment, the target protein is only MLH1.

[0367] Displacement assays are well known in the art. In embodiments of the invention where Q is a fluorophore, the displacement assay is a fluorescence polarization assay. Fluorescence polarization assays are well known in the art.

[0368] The test compound can be any biological or small molecule compound screened for binding to the ATP binding site of a target protein (eg, MLH1 or PMS2).

[0369] In another aspect, the present invention provides an assay for determining the binding affinity of a test molecule to an ATP-binding site of a target protein, the assay comprising: (i) incubating a test molecule with a target protein in the presence of a probe compound of Formula I, II, I-II or I-III, or a salt thereof, as defined herein; (ii) determining whether any of the probe compounds displaces the ATP binding site of the target protein; Includes.

[0370] In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a particular embodiment, the target protein is MLH1 and PMS2. In a particular embodiment, the target protein is only MLH1.

[0371] Suitably, the assay is a displacement assay. Displacement assays are well known in the art. In embodiments of the invention where Q is a fluorophore, the displacement assay is a fluorescence polarization assay. Fluorescence polarization assays are well known in the art.

[0372] Determining whether any probe compound is displaced from the ATP-binding site of the target protein suitably comprises detecting whether the test compound results in an increase in the proportion of probe compound of Formula I, II, I-II, or I-III that is not bound to the ATP-binding site. This can be achieved by detecting whether there is an increase (relative to a control) in the amount of unbound probe compound, or, if the amount of bound probe compound can be easily detected (e.g., by fluorescence polarization), whether there is a decrease (again relative to a control) in the amount of bound probe compound.

[0373] The proportion of probe compound bound to the amount not bound to the ATP binding site of target protein can be determined by techniques known in the art.The specific technique used depends on the nature of the detection moiety Q in the compound of formula I, II, I-II or I-III.Suitably, Q is a fluorophore, and the assay is a fluorescence polarization assay.In this assay, the difference in fluorescence caused by the displacement of probe compound from the ATP binding site of target protein can be detected and used to quantify the amount of any displaced probe compound, thereby determining the binding affinity of test compound to the ATP binding site of target protein.

[0374] In another aspect, the present invention provides a method for determining the binding affinity of a test molecule to an ATP-binding site of a target protein, the assay comprising: (i) incubating a test molecule with a target protein in the presence of a probe compound of Formula I, II, I-II or I-III, or a salt thereof, as defined herein; (ii) determining whether any of the probe compounds displaces the ATP binding site of the target protein; Includes.

[0375] In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a particular embodiment, the target protein is MLH1 and PMS2. In a particular embodiment, the target protein is only MLH1.

[0376] Suitably, the method is a displacement assay. Displacement assays are well known in the art. In embodiments of the invention where Q is a fluorophore, the displacement assay is a fluorescence polarization assay. Fluorescence polarization assays are well known in the art.

[0377] The step of determining whether any probe compound is displaced from the ATP binding site of the target protein can be carried out in the manner described above.

[0378] In another aspect, the present invention provides an assay for determining the location and / or abundance of a target protein present in a biological sample, the assay comprising: (i) contacting a biological sample with a probe compound of Formula I, II, I-II, or I-III, or a salt thereof, as defined herein; (ii) determining the location and / or amount of a compound of Formula I, II, I-II, or I-III present in a biological sample by detecting the location and / or intensity of a detectable moiety of a compound of Formula I present in the sample; Includes.

[0379] In another aspect, the present invention provides an assay for determining the location and / or abundance of a target protein present in a biological sample, the assay comprising: (i) R, as defined herein 12 or R 13 -L as defined herein x contacting the biological sample with a probe compound of formula I, II, I-II or I-III, or a salt thereof, wherein -X is a group; (ii) reacting in situ within a biological sample with a functional group X present in a compound of formula I, II, I-II, or I-III to form R 12 or R 13 contacting the biological sample with a detection moiety, Q, as defined herein, or a compound of formula Q-L2-Y, which is capable of forming a compound of formula I, II, I-II or I-III, wherein one of is a -LQ group as defined herein; (iii) determining the location and / or amount of the compound of formula I present in the biological sample by detecting the location and / or intensity of the detectable moiety of the compound of formula I, II, I-II, or I-III present in the sample; Includes.

[0380] In another aspect, the present invention provides a method for determining the location and / or abundance of a target protein present in a biological sample, the method comprising: (i) contacting a biological sample with a probe compound of Formula I, II, I-II, or I-III, or a salt thereof, as defined herein; (ii) determining the location and / or amount of the compound of formula I, II, I-II or I-III present in the biological sample by detecting the location and / or intensity of the detectable moiety of the compound of formula I, II, I-II or I-III present in the sample; Includes.

[0381] In another aspect, the present invention provides a method for determining the location and / or abundance of a target protein present in a biological sample, the method comprising: (i) In situ R in biological samples 12 or R 13 -L as defined herein x-X group, reacting with the functional group X present in the compound of formula I, II, I-II or I-III to form R 12 or R 13 contacting the biological sample with a detection moiety, Q, as defined herein, or a compound of formula Q-L2-Y, which is capable of forming a compound of formula I, II, I-II or I-III, wherein one of is a -LQ group as defined herein; (ii) determining the location and / or amount of a compound of Formula I, II, I-II, or I-III present in a biological sample by detecting the location and / or intensity of a detectable moiety of a compound of Formula I present in the sample; Includes.

[0382] In one embodiment, the target protein is selected from MLH1 or MLH1 and PMS2. In a particular embodiment, the target protein is MLH1 and PMS2. In a particular embodiment, the target protein is only MLH1.

[0383] Suitably, the step of contacting the biological sample with a probe compound of formula I, II, I-II or I-III (step (i) in the above assays and methods) comprises incubating the biological sample with the probe compound under conditions that allow it to bind to the ATP binding site of the target protein (e.g., MLH1 or MLH1 and PMS2).

[0384] The determination of the distribution and content of the compound of formula I in a biological sample can be achieved by techniques known in the art. The specific technique used depends on the nature of the detection moiety Q in the compound of formula I. Suitably, Q is a fluorophore, and the determination of the location and content of the compound of formula I in the sample can be achieved by fluorescence microscopy / imaging. Appropriate calibration of fluorescence intensity can be used to determine the content of the compound of formula I at various locations in the sample.

[0385] The assays and methods of the invention defined herein may optionally further comprise one or more washing steps carried out after step (i) to remove excess probe compounds of formula I, II, I-II or I-III from the biological sample. [Example]

[0386] <abbreviation> Boc is tert-butyloxycarbonyl DAST is diethylaminosulfur trifluoride DBU is 1,8-diazabicyclo(5.4.0)undec-7-ene DCC is dicyclohexylcarbodiimide DCE is 1,1-dichloroethane DCM is dichloromethane DEA is diethanolamine DEAD is diethyl azodicarboxylate DIAD is diisopropyl azodicarboxylate DIBAL is diisobutylaluminum hydride DIPEA is N,N-diisopropylethylamine, Hunig's base DMA is N,N-dimethylacetamide DMAP is 4-(dimethylamino)pyridine DMF is N,N-dimethylformamide DMSO is dimethyl sulfoxide. EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc is ethyl acetate h is the time HATU is N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU is (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate HOBT is N-hydroxybenzotriazole HPLC is high pressure liquid chromatography. LAH is lithium aluminum hydride IPA is isopropyl alcohol LCMS is liquid chromatography-mass spectrometry LDA is lithium diisopropylamide LiHMDS is lithium bis(trimethylsilyl)amide mCPBA is meta-chloroperbenzoic acid MI is the molecular ion Min is minutes MgSO4 Anhydrous Magnesium Sulfate MW is microwave NBS is N-bromosuccinamide NCS is N-chlorosuccinamide NFOBS is N-fluoro-o-benzenedisulfonimide NFSI is N-fluorobenzenesulfonimide NHS is N-hydroxysuccinimide NIS is N-iodosuccinamide NMM is N-methylmorpholine NMP is 1-methyl-2-pyrrolidinone NMR is nuclear magnetic resonance. PdCl2(PPh3)2 is bis(triphenylphosphine)palladium chloride Pd(dppf)2Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Pd(dppf)2Cl2.DCM is the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (Pd(dba)2) is bis(dibenzylideneacetone)palladium Rbf is a round bottom flask RT is retention time. SCX-2 is a silica-based sorbent with chemically bonded propylsulfonic acid functional groups. SFC stands for supercritical fluid chromatography STAB is sodium triacetoxyborohydride TBAF is tetra-n-butylammonium fluoride TBDMS is tert-butyldimethylsilyl TFAA is trifluoroacetic anhydride TFA is trifluoroacetic acid THF is tetrahydrofuran TPP is tripotassium phosphate Ts is toluenesulfonyl XPhos-Pd-G1 is 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride XPhos-Pd-G2 is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0387] <Analysis method> Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash or glass column chromatography was performed using Merck silica gel 230-400 mesh size. Column chromatography was also performed using glass column chromatography or flash chromatography. Flash chromatography was performed on a combi-flash RF Teledyne Isco instrument. Preparative TLC was performed on Merck plates. 1H NMR spectra were recorded on a Bruker Avance-400 or Bruker Avance III 400 MHz. Samples were prepared as solutions in suitable deuterated solvents and referenced to the appropriate internal non-deuterated solvent peak or tetramethylsilane; chemical shifts are reported in ppm (δ) downfield from tetramethylsilane. Flash chromatography was also performed on a combi-flash RF Teledyne Isco instrument. Preparative TLC was performed on Merck plates.

[0388] <Liquid chromatography-mass spectrometry> Method A Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA performance mass detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 micron; Column temperature: 35 °C; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% formic acid in water (v / v):acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV; source and probe temperatures were 120 °C and 600 °C, respectively.

[0389] Method B Waters Acquity with PDA detector and SQ Detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 micron; Column temperature: 35 °C; Autosampler 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 rate: 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow rate: 0.5 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.5 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 0.7 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 0.7 mL / min; Gradient to t = 3.51 min (97% A, 3% B) Flow rate: 0.5 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time: 4 min. Mass detection parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 3.25 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[0390] Method C 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; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% formic acid in water (v / v):acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV; source and probe temperatures were 120 °C and 600 °C, respectively.

[0391] Method D Waters Acquity UPLC with quaternary solvent manager, PDA detector, and SQ detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 micron; Column temperature: 35 °C; Autosampler 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 rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ESI capillary probe, ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[0392] Method E 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; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% formic acid in water (v / v):acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV; source and probe temperatures were 120 °C and 600 °C, respectively.

[0393] Method F Waters Acquity UPLC with PDA detector and SQ Detector; Column: Welch-Xtimate, C18 4.6 x 50 mm, 5 micron; Column temperature: 35 °C; Autosampler 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 rate: 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow rate: 0.5 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.5 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 0.7 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 0.7 mL / min; Gradient to t = 3.51 min (97% A, 3% B) Flow rate: 0.5 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time: 4 min. Mass detection parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 3.25 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[0394] Method G Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA performance mass detector; Column: X-Bridge C18 2.1 x 50 mm 3.5 micron; Column temperature: 35 °C; Autosampler 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 rate: 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow rate: 0.5 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.5 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 0.7 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 0.7 mL / min; Gradient to t = 3.51 min (97% A, 3% B) flow rate: 0.7 mL / min B) Flow rate: 0.5 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV, source and probe temperatures were 120 °C and 600 °C, respectively.

[0395] Method H Waters Acquity with PDA detector and SQ Detector. Column: X-bridge C18, 50 × 4.6 mm, 3.5 micron. Column temperature: 25 °C. Mobile phase A: 5 mM ammonium bicarbonate in ddH2O (pH = 7.35). Mobile phase B: MeOH. Mobile phase gradient details: t = 0 min (92% A, 8% B); t = 0.75 min (92% A, 8% B); gradient to t = 3 min (30% A, 70% B); gradient to t = 3.75 min (5% A, 95% B); gradient to t = 4.20 min (0% A, 100% B); t = 5.20 min (0% A, 100% B); gradient to t = 5.21 min (92% A, 8% B); t = 7 min (92% A, 8% B). The run ended at B), flow rate: 1 mL / min, analysis time: 7 min. Mass detector parameters: ionization mode cycles in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 3.25 kV, and source and probe temperatures were 120 °C and 600 °C, respectively.

[0396] Method I Acquity UPLC (binary pump / PDA detector) coupled to a Waters ZQ mass spectrometer. Column: Acquity UPLC BEH Shield RP18 1.7 μm 100 × 2.1 mm (Plus guard cartridge) maintained at 40 °C. Mobile phase: MeCN in water (containing 10 mM ammonium bicarbonate) from 5% to 95% in 6 min; flow rate: 0.5 ml / min; wavelength: 210–400 nm DAD.

[0397] Method J LC / MS was performed on an Acquity UPLC (binary pump / PDA detector) coupled to a Waters ZQ mass spectrometer. Column: Acquity UPLC HSS C18 1.8 μm 100 × 2.1 mm (Plus guard cartridge) maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid) from 5% to 95% in 6 min; flow rate: 0.5 ml / min; wavelength: 210–400 nm DAD.

[0398] <Analytical HPLC method> Method A Agilent 1100 Series instrument equipped with a PDA detector, Sunfire (C18 150 mm × 4.6 mm) 3.5 μm column, temperature: 25 °C; autosampler temperature: 25 °C; mobile phase A: 0.05% trifluoroacetic acid in Milli-Q water (pH = 2.1); mobile phase B: 100% 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); run termination at T = 17 min (90% A, 10% B); flow rate: 1.0 mL / min; run time: 17 min.

[0399] Method B Agilent 1260 Series instrument equipped with a PDA detector, Sunfire C18 (150 mm × 4.6 mm) 3.5 μm column, temperature: 25 °C; autosampler temperature: 25 °C; mobile phase A: 0.05% trifluoroacetic acid in Milli-Q water (pH = 2.1); mobile phase B: 100% 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); run termination at T = 17 min (90% A, 10% B); flow rate: 1.0 mL / min; run time: 17 min.

[0400] Method C Waters Alliance e2695 instrument equipped with a 2998 PDA detector, an Atlantis C18 (150 mm × 4.6 mm) 5 μm column, temperature: 25 °C; autosampler temperature: 25 °C. Mobile phase A: 0.1% ammonium hydroxide solution in HPLC water. Mobile phase B: 100% 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); run termination at T = 17 min (90% A, 10% B). Flow rate: 1.0 mL / min; run time: 17 min.

[0401] NMR Using a Bruker Avance-400 instrument operating at 400 MHz with the solvents indicated at room temperature unless otherwise stated. 1H nuclear magnetic resonance (NMR) spectroscopy was performed. Samples were prepared as solutions in suitable deuterated solvents and referenced to the appropriate internal non-deuterated solvent peak or to tetramethylsilane. Chemical shifts were reported in ppm (δ) downfield from tetramethylsilane. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are indicated in parts per million using conventional abbreviations for the major peak designations: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; and br, broad.

[0402] <Purification method> Preparative HPLC purification Preparative HPLC Method-A Shimadzu Prep-20-AD with a binary pump equipped with a UV / visible wavelength detector; Column: C18, 250 × 20 mm, 5 micron; Column temperature: room temperature; Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile:methanol:2-propanol (65:25:10); Mobile phase gradient details: t = 0 min (55% A, 45% B); t = 17 min (55% A, 45% B); gradient to t = 17.01 min (2% A, 98% B); t = 19 min (2% A, 98% B); gradient to t = 19.01 min (55% A, 45% B); run termination at t = 21 min (55% A, 45% B); Flow rate: 27 mL / min; Analysis time: 21 min.

[0403] Preparatory HPLC Method-B Shimadzu Prep-20-AD with a binary pump equipped with a UV / visible wavelength detector; Column: C18, 250 × 20 mm, 5 micron; Column temperature: room temperature; Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile; Mobile phase gradient details: t = 0 min (72% A, 28% B); t = 19 min (72% A, 28% B); gradient to t = 19.01 min (2% A, 98% B); t = 21 min (2% A, 98% B); gradient to t = 21.01 min (72% A, 28% B); run termination at t = 24 min (72% A, 28% B); Flow rate: 20 mL / min; Analysis time: 24 min.

[0404] Preparative HPLC Method-C Sample purification was performed on an Agilent Series 1260 Infinity-II Purification System equipped with a PDA detector; column: Waters Sunfire C18, 150 × 4.6 mm, 3.5 micron; column temperature: room temperature; autosampler temperature: 15 °C; mobile phase A: 0.05% (v / v) trifluoroacetic acid in Milli-Q water (pH ∼2.5); mobile phase B: 100% acetonitrile; mobile phase gradient details: t = 0 min (90% A, 10% B); gradient (10% A, 90% B) to t = 7 min; gradient (0% A, 100% B) to t = 9 min; gradient (0% A, 100% B) to t = 14 min; gradient (90% A, 10% B) to t = 14.01 min; run termination at t = 17 min (90% A, 10% B) unless otherwise noted; flow rate: 1 mL / min; analysis time: 17 min.

[0405] Preparatory HPLC Method-D Sample purification was performed on an Agilent Technologies 1260 Infinity Purification System and an Agilent 6120 Series Single Quadrupole Mass Spectrometer; column: Waters X-bridge Phenyl 100 x 19 mm, 10 μm internal diameter; mobile phase: MeOH (0.1% (NH4)2CO3) in water; flow rate: 20 ml / min; wavelength: 210-400 nm. Samples were injected in DMSO, with a 23-minute nonlinear gradient from 5% to 100% MeCN centered on a specific focused gradient.

[0406] Preparative HPLC Method-E Chromatographic separation and isolation were performed using a Waters 2545 quaternary column equipped with a Waters 2489 UV detector. The column used was a YMC-ODS AQ C18-s, 250 × 20 mm, 5 micron column. The compounds were eluted with mobile phase A: 0.1% formic acid in water, mobile phase B: 20% mobile phase A in acetonitrile, with a gradient of T = 0 min (50% A, 50% B), T = 23.0 min (50% A, 50% B), T = 23.01 min (2% A, 98% B), T = 26.00 min (2% A, 98% B), T = 26.01 min (50% A, 50% B), and T = 29.00 min (50% A, 50% B). Flow rate = 16 mL / min; analysis time 29 min.

[0407] Preparative HPLC Method-F Chromatographic separation and isolation were performed using a Shimadzu LC20AP equipped with a UV detector. The column used was a Repack C18, 5 micron. The compounds were eluted with mobile phase A: water and mobile phase B: acetonitrile, with a gradient of T = 0 min (60% A, 40% B), followed by a gradient of T = 17.0 min (40% A, 60% B), T = 17.01 min (2% A, 98% B), T = 19.00 min (2% A, 98% B), T = 19.01 min (60% A, 40% B), and T = 22.00 min (60% A, 40% B). The flow rate was 25 mL / min, and the analysis time was 22 min.

[0408] Preparative HPLC Method-G Chromatographic separation and isolation were carried out using a Biotage flash chromatography system equipped with a UV detector. The column used was a YMC C18 120 gm, 50 micron column. The compounds were eluted with mobile phase A: 0.1% formic acid in Milli Q water, mobile phase B: acetonitrile, with a gradient of T = 0 min (100% A, 0% B); gradient T = 5.0 min (100% A, 0% B); gradient (60% A, 40% B) to T = 40.0 min; gradient (0% A, 100% B) to T = 45.00 min; gradient (0% A, 100% B) to T = 45.01 min (100% A, 0% B); gradient (100% A, 0% B) to T = 50.00 min; flow rate = 80 mL / min; analysis time 50 min.

[0409] Preparatory HPLC Method -H Chromatographic separation and isolation were performed using a Shimadzu LC20AP equipped with a UV detector. The column used was a Sunfire prep C18 OBD, 250 × 19 mm, 5 micron. The compounds were eluted with mobile phase A: 0.1% formic acid in water and mobile phase B: acetonitrile, with a gradient of T = 0 min (88% A, 12% B), followed by a gradient of T = 20.0 min (82% A, 18% B), T = 20.01 min (2% A, 98% B), T = 23.00 min (2% A, 98% B), T = 23.01 min (88% A, 12% B), and T = 27.00 min (88% A, 12% B). The flow rate was 22 mL / min, and the analysis time was 27 min.

[0410] Preparative HPLC Method-I Chromatographic separation and isolation were carried out using a Biotage flash chromatography system equipped with a UV detector. The column used was a YMC C18 120 gm, 50 micron column. The compounds were eluted with mobile phase A: 0.1% formic acid in Milli Q water, mobile phase B: acetonitrile, with a gradient of T = 0 min (100% A, 0% B); gradient T = 5.0 min (95% A, 5% B); gradient T = 30.0 min (60% A, 40% B); gradient T = 30.01 min (0% A, 100% B); gradient T = 35.00 min (0% A, 100% B); gradient T = 35.01 min (100% A, 0% B); gradient T = 40.00 min (100% A, 0% B); flow rate = 80 mL / min; analysis time 40 min.

[0411] Preparative HPLC Method-J Chromatographic separation and isolation were performed using a Waters 2545 quaternary column equipped with a Waters 2489 UV detector. The column used was an X-bridge prep C18 OBD 250 × 19 mm, 5 micron. The compounds were eluted with mobile phase A: 0.1% formic acid in water, mobile phase B: 20% acetonitrile, with a gradient of T = 0 min (95% A, 5% B); gradient T = 2.0 min (80% A, 20% B); gradient T = 22.0 min (76% A, 24% B); gradient T = 22.01 min (2% A, 98% B); gradient T = 24.00 min (2% A, 98% B); gradient T = 24.01 min (70% A, 30% B); gradient T = 28.00 min (95% A, 5% B); flow rate = 23 mL / min; analysis time 28 min.

[0412] Preparative HPLC Method-K Chromatographic separation and isolation were performed using a Waters 2545 quaternary column equipped with a Waters 2489 UV detector. The column used was an X-bridge prep C18 OBD 250 × 19 mm, 5 micron. The compounds were eluted with mobile phase A: 0.1% formic acid in water and mobile phase B: acetonitrile, with a gradient of T = 0 min (92% A, 8% B), followed by a gradient of T = 15.0 min (68% A, 32% B), followed by a gradient of T = 15.01 min (2% A, 98% B), followed by a gradient of T = 17.00 min (2% A, 98% B), followed by a gradient of T = 17.01 min (68% A, 32% B), followed by a gradient of T = 20.00 min (68% A, 32% B), with a flow rate of 20 mL / min and a run time of 20 min.

[0413] Preparative HPLC Method-L Chromatographic separation and isolation was performed using a Waters 2545 quaternary system equipped with a Waters 2489 UV detector. The column used was a Sunfire prep C18 OBD 150 x 19 mm, 5 micron, and the compounds were eluted with mobile phase A: 0.1% formic acid in water, mobile phase B: 20% mobile phase A + 5% tetrahydrofuran in acetonitrile, with a gradient of T = 0 min (70% A, 30% B); gradient T = 2.0 min (57% A, 43% B); gradient to T = 21.0 min (57% A, 43% B); gradient to T = 21.01 min (2% A, 98% B); gradient to T = 23.00 min (2% A, 98% B); gradient to T = 23.01 min (70% A, 30% B); gradient to T = 25.00 min (70% A, 30% B); flow rate = 21 mL / min; analysis time 25 min.

[0414] Preparative HPLC Method-M Chromatographic separation and isolation were carried out using a Biotage flash chromatography system equipped with a UV detector. The column used was a YMC C18 120 gm, 50 micron column. 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 (100% A, 0% B), T = 35.0 min (65% A, 35% B), T = 35.01 min (2% A, 98% B), T = 38.00 min (2% A, 98% B), T = 38.01 min (100% A, 0% B), T = 40.00 min (100% A, 0% B), and T = 40.00 min (100% A, 0% B). Flow rate = 80 mL / min; analysis time 40 min.

[0415] <Chiral preparative HPLC method> The enantiomeric separation of the compounds was achieved by chiral preparative HPLC purification. Below is a list of chiral preparative HPLC purification methods and conditions used to resolve enantiomers or determine enantiomeric purity (ee).

[0416] JPEG2024528693000029.jpg226170

[0417] For Examples 110 and 111: NanoBRET® 590 SE, NanoBRET® 590-O4-SE, and NanoBRET® 590-C4-SE were obtained from Promega Corp., Madison, WI. Mass spectra were recorded on a Thermo Fisher Vanquish™ (LC-MS), and purity (≥95%) was determined by reverse-phase high-pressure liquid chromatography (RP-HPLC) using a Kinetex 5 μm EVO C18 100Å LC column, 30×2.1 mm, or a Phenomenex Synergi 2.5 μm Max-RP 100Å LC column. Compounds were purified on a Waters LC Prep 150 using a Waters XBridge Prep C18 OBD 30×250 mm column. Method 1: Initial - 90% aqueous (0.1% TFA in H2O), 10% acetonitrile to 0% aqueous, 100% acetonitrile, linear gradient in 30 min.

[0418] <Synthesis> Several methods for the chemical synthesis of the compounds of the present application are described herein. These and / or other well-known methods may be variously modified and / or adapted to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood to be within the spirit and scope of the present application and claims. Therefore, the methods described in the following description, schemes, and examples are for illustrative purposes only and should not be construed as limiting the scope of the present disclosure.

[0419] In one approach (Scheme 1), compounds of formula [I] may be prepared by reacting a substituted aromatic carboxylic acid of formula [II] with an amine of general formula [III] in the presence of oxalyl chloride or thionyl chloride in a solvent such as DCM and a tertiary amine base such as EtN, DIPEA, or NMM. The reaction is suitably carried out at RT. After reaction workup (typically by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method A). Compounds of formula [I] may also be prepared by reacting a substituted aromatic carboxylic acid of formula [II] with an amine of general formula [III] and a suitable coupling agent such as HOBT / EDC, HBTU, or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EtN, DIPEA, or NMM. After reaction workup (typically by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method B). The bistosyl-protected intermediate (from Method A or B) is then subjected to deprotection with a suitable base, such as K2CO3 or KOH, in a suitable protic solvent, such as MeOH or EtOH. The reaction is suitably carried out at elevated temperature. After reaction workup (typically by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization to give a compound of general formula [I].

[0420] [ka]

[0421] [Example 1]: (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydro-isoquinolin-2(1H)-yl)methanone [ka]

[0422] Step-1: t-butyl (R)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate A stirred solution of t-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.70 g, 2.24 mmol, 1 eq) (CAS: 893566-75-1), (R)-tetrahydrofuran-3-amine (0.234 g, 2.68 mmol, 1.5 eq) (CAS: 111769-26-7), and NaOtBu (0.537 g, 5.60 mmol, 2.5 eq) in 1,4-dioxane (7 mL) in a 35 mL microwave sealed tube was degassed using N gas for 15-20 min. Brettphos (0.007 g, 0.013 mmol, 0.006 eq) and Pd(dba) (0.006 g, 0.006 mmol, 0.003 eq) were added to the reaction mixture at room temperature. The resulting reaction mixture was heated to 120° C. under microwave irradiation for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (the product was eluted in 15% EtOAc in hexane) to give the title compound (0.430 g, yield: 56.1%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 1.42 (s, 9H), 1.74 (m, 1H), 1.84 - 1.85 (m, 1H), 2.14 - 2.19 (m, 1H), 2.66 - 2.68 (m, 2H), 3.33 - 3.50 (m, 2H), 3.56 - 3.59 (m, 1H), 3.69 - 3.74 (m, 1H), 3.80 - 3.85 (m, 1H), 3.90 - 3.93 (m, 1H), 3.99 - 4.05 (m, 1H), 4.27 (s, 2H), 4.84 (bs, 1H), 6.45 (d, J= 8 Hz, 2H), 6.99 (t, J= 8 Hz, 15.6 Hz, 1H). LCMS (Method A): 2.127 min, MS: ES+ 263.10 (M-56).

[0423] Step-2: (R)-N-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-amine hydrochloride (Intermediate 40) A stirred solution of t-butyl (R)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.4 g, 1.25 mmol, 1.0 eq) in DCM (4 mL) was cooled to 0 °C and 4 M HCl in dioxane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the crude material was triturated with diethyl ether (2 × 50 mL) followed by n-pentane (3 × 50 mL). The resulting solid material was dried under high vacuum to give the title compound (0.36 g, quantitative) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 1.84 - 1.91 (m, 1H), 2.13 - 2.22 (m, 1H), 2.92 - 2.95 (m, 2H), 3.25 - 3.38 (m, 2H), 3.62 - 3.74 (m, 2H), 3.82 - 3.92 (m, 2H), 3.99 - 4.03 (m, 3H), 6.58 - 6.64 (m, 2H), 7.03 - 7.12 (m, 1H), 9.83 (bs, 2H). LCMS (Method A): 0.882 min, MS: ES+ 219.14 (M+1).

[0424] Step-3: (R)-5-(benzyloxy)-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) A stirred solution of 2-(benzyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 61) (0.50 g, 0.88 mmol, 1 eq) in DMF (5 mL) at 0 °C was treated with HATU (0.501 g, 1.32 mmol, 1.5 eq) and DIPEA (0.23 g, 1.78 mmol, 2 eq), and the mixture was stirred (10 min). (R)-N-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-amine hydrochloride (Intermediate 40) (0.228 g, 1.04 mmol, 1.2 eq) was added to the reaction mixture at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h, poured into water (100 mL), and extracted with ethyl acetate (3 × 120 mL). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (product was eluted in 25% EtOAc in hexanes) to give the title compound (0.380 g, 59.2% yield) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz). LCMS (Method A): 2.652 min, 2.768 min, MS: ES+ 769.2 (M+1).

[0425] Step-4: (R)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone A stirred solution of (R)-5-(benzyloxy)-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.350 g, 0.45 mmol, 1 eq.) in EtOH:HO (1:1) at room temperature was treated with KOH (1.021 g, 18.19 mmol, 40 eq.). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was poured into water (100 mL), acidified using 1 N HCl solution (pH ∼6), and extracted into ethyl acetate (3 × 120 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (product was 3.5% in DCM). The mixture was purified by column chromatography (eluted with MeOH) to give the title compound (0.08 g, 33% yield) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz, 346K): δ 1.85 - 1.87 (m, 1H), 2.17 - 2.22 (m, 1H), 2.67 - 2.69 (m, 2H), 3.46 - 3.57 (m, 2H), 3.59 - 3.71 (m, 1H), 3.73 - 3.76 (m, 1H), 3.84 - 3.91 (m, 1H), 3.95 - 4.01 (m, 1H), 4.04 - 4.10 (m, 1H), 4.40 - 4.60 (m, 2H), 4.97 (s, 2H), 6.01 (s, 1H), 6.43 - 6.50 (m, 2H), 6.99 (t, J= 8.4 Hz, 1H), 7.25 - 7.26 (m, 5H), 9.19 - 9.22 (m, 2H). LCMS (Method A): 1.813 min, MS ES+ 461.12 (M+1).

[0426] [Example 2]: (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydro-isoquinolin-2(1H)-yl)methanone [ka]

[0427] Step-1: t-butyl (S)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate A stirred solution of t-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.6 g, 1.92 mmol, 1.0 eq) (CAS: 893566-75-1), (S)-tetrahydrofuran-3-amine hydrochloride (0.35 g, 2.88 mmol, 1.5 eq) (CAS: 204512-95-8), and NaOtBu (0.46 g, 4.8 mmol, 2.5 eq) in 1,4-dioxane (8 mL) at room temperature was treated with Brettphos (0.06 g, 0.11 mmol, 0.06 eq) under a nitrogen atmosphere at room temperature. 2(g) The mixture was degassed using HCl for 15 minutes. Pd2(dba)3 (0.07 g, 0.07 mmol, 0.04 eq) was added and the reaction mixture was stirred at 120 °C under microwave irradiation for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (the product was eluted with 5% EtOAc in hexane) to give the title compound (0.36 g, yield: 58.8%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 1.43 (s, 9H), 1.84 - 1.91 (m, 1H), 2.13 - 2.22 (m, 1H), 2.66 - 2.69 (m, 2H), 3.37 - 3.50 (m, 2H), 3.56 - 3.59 (m, 1H), 3.69 - 3.74 (m, 1H), 3.80 - 3.85 (m, 1H), 3.90 - 3.93 (m, 1H), 3.99 - 4.05 (m, 1H), 4.27 (s, br, 2H), 4.84 (s, br, 1H), 6.45 (d, J= 8 Hz, 2H), 6.99 (t, J= 8 Hz, 15.6 Hz, 1H). LCMS (Method A): 2.122 min, MS: ES+ 263.10 (M-56).

[0428] Step-2: (S)-N-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-amine hydrochloride (Intermediate 39) A stirred solution of t-butyl (S)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.31 g, 0.97 mmol, 1.0 eq) in DCM (5 mL) was cooled to 0° C. 4 M HCl in dioxane (3 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 1 h, concentrated in vacuo, and the crude solid material was triturated with diethyl ether (3×10 mL) and further dried under high vacuum to give the title compound (0.22 g, yield: 98.76%, 1.00 mmol). 1 H NMR (DMSO-d6, 400 MHz): 1.81- 1.90 (m, 1H), 2.13 - 2.22 (m, 1H), 2.92 - 2.93 (m, 2H), 3.26 - 3.27 (m, 2H), 3.58 - 3.60 (m, 2H), 3.70 - 3.74 (m, 1H), 3.80 - 3.89 (m, 1H), 3.90 - 4.01 (m, 3H), 6.51 - 6.75 (m, 2H), 7.03 - 7.10 (m, 2H), 9.47 - 9.67 (bs, 2H). LCMS (Method B): 2.11 minutes, MS: ES+ 219.3 (M+1).

[0429] Step-3: (S)-5-(benzyloxy)-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) A stirred solution of 2-(benzyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 61) (0.42 g, 0.739 mmol, 1.0 eq) in DMF (10 mL) at 0 °C was treated with DIPEA (0.19 g, 1.47 mmol, 2.0 eq) and HATU (0.42 g, 1.10 mmol, 1.5 eq) and stirred for 5 min. (S)-N-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-8-amine hydrochloride (Intermediate 39) (0.209 g, 0.96 mmol, 1.3 eq) was added, and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (product eluted with 15% EtOAc in hexanes) to give the title compound (0.6 g, yield: quantitative, 0.78 mmol). LCMS (Method A): 2.659 min, 2.733 min. MS: ES+ 769.06 (M+1).

[0430] Step-4: (S)-(2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone A stirred solution of (S)-5-(benzyloxy)-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.5 g, 0.65 mmol, 1.0 eq) in EtOH:HO (7:3) (15 mL) at room temperature was treated with KOH (1.46 g, 26.01 mmol, 40 eq). The reaction mixture was heated to 60° and stirred for 2 h. The reaction mixture was cooled to 0 °C, acidified using saturated KHSO solution, and extracted using ethyl acetate (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography followed by preparative TLC (5% MeOH in DCM) to give the title compound (0.035 g, yield: 11.7%, 0.075 mmol) as an off-white solid.1 H NMR (DMSO-d6, 400 MHz, 346K): δ 1.87 (s, 1H), 2.17 - 2.22 (m, 1H), 2.69 - 2.84 (m, 2H), 3.46 - 3.53 (m, 2H), 3.58 - 3.71 (m, 1H), 3.71 - 3.76 (m, 1H), 3.83 - 3.91 (m, 1H), 3.93 - 3.95 (m, 1H), 3.95 - 4.03 (m, 1H), 4.42 - 4.67 (m, br, 2H), 4.97 - 5.00 (m, 2H), 5.98 - 6.01 (m, 2H), 6.43 - 6.50 (m, 2H), 6.99 (t, J= 8.0 Hz, 1H), 7.25 - 7.37 (m, 5H), 9.20 (s, 2H). LCMS (Method A): 1.807 min, MS ES+ 461.17 (M+1).

[0431] Unless otherwise stated, the examples in Table 1 were prepared following the procedures described for Examples 1 and 2 using the indicated amine and 2-(benzyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 61), followed by protecting group removal.

[0432] JPEG2024528693000033.jpg252170 JPEG2024528693000034.jpg247170 JPEG2024528693000035.jpg255162 JPEG2024528693000036.jpg223170 JPEG2024528693000037.jpg209170 JPEG2024528693000038.jpg245170 JPEG2024528693000039.jpg166170 JPEG2024528693000040.jpg190170 JPEG2024528693000041.jpg198170 JPEG2024528693000042.jpg249170 JPEG2024528693000043.jpg202170 JPEG2024528693000044.jpg237170 JPEG2024528693000045.jpg166170 JPEG2024528693000046.jpg222170 JPEG2024528693000047.jpg236170 JPEG2024528693000048.jpg252170 JPEG2024528693000049.jpg225170 JPEG2024528693000050.jpg212170 JPEG2024528693000051.jpg238170 JPEG2024528693000052.jpg173170 JPEG2024528693000053.jpg244170 JPEG2024528693000054.jpg224170 JPEG2024528693000055.jpg216170 JPEG2024528693000056.jpg197170 JPEG2024528693000057.jpg182170 JPEG2024528693000058.jpg255164 JPEG2024528693000059.jpg205170 JPEG2024528693000060.jpg180170 JPEG2024528693000061.jpg230170 JPEG2024528693000062.jpg255170 JPEG2024528693000063.jpg174170JPEG2024528693000064.jpg237170JPEG2024528693000065.jpg191170JPEG2024528693000066.jpg184170JPEG202 4528693000067.jpg175170JPEG2024528693000068.jpg233170JPEG2024528 693000069.jpg212170JPEG2024528693000070.jpg228170JPEG20245286930 00071.jpg198170JPEG2024528693000072.jpg239170JPEG2024528693000073.jpg220170JPEG2024528693000074.jpg183170JPEG2024528693000075.j pg190170JPEG2024528693000076.jpg196170JPEG2024528693000077.jpg217170JPEG2024528693000078.jpg212170JPEG2024528693000079.jpg117170

[0433] [Example 79] (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-((methylamino)methyl)isoindolin-2-yl)methanone [ka]

[0434] Isoindoline-4-carbaldehyde hydrochloride A stirred solution of t-butyl 4-formylisoindoline-2-carboxylate (Intermediate 58) (0.5 g, 2.02 mmol, 1.0 eq.) in DCM (5 mL) at 0° C. was treated with 4 M HCl in dioxane (2.5 mL) and stirred for 1 h. The resulting reaction mixture was evaporated and triturated with diethyl ether (20 mL) to give the title compound (0.371 g, 100% yield) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 4.53 (s, 2H), 4.76 (s, 2H), 7.67 (t, J= 7.6 Hz, 1H), 7.75 (d, J= 7.2 Hz, 1H), 7.99 (d, J= 7.2 Hz, 1H), 9.86 (s, 2H), 10.0 (s, 1H). LCMS (Method B): 1.54 min, MS: ES +148.21 (M+1).

[0435] 5-(Benzyloxy)-4-(4-formylisoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 59) A stirred solution of 2-(benzyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 61) (0.4 g, 0.70 mmol, 1.0 eq) in DMF (2 mL) at 0°C–5°C was treated with HATU (0.400 g, 1.05 mmol, 1.5 eq) and DIPEA (0.453 g, 3.51 mmol, 5.0 eq) and stirred for 10 min. Isoindoline-4-carbaldehyde hydrochloride (0.155 g, 0.84 mmol, 1.2 eq.) in DMF (1 mL) was added dropwise at 0–5°C. The resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was poured into ic...

Claims

1. The structural formula (I) shown below: 【Chemical 1】 Formula (I) [In the formula,[[]] R ２ is hydrogen or fluoro; R ４ is hydrogen or fluoro; R ６ is (1-6C) alkyl, (3-8C) cycloalkyl, or a 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, Or a group having a structure according to formula (A) shown below: 【Chemical 2】 [In the formula,[[]] R ７ is hydrogen or (1-3C) alkyl; n is 1 or 2; R ８ is (3-8C) cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more R ９ groups; each R ９ is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (1-3C) haloalkyl, or (1-3C) haloalkoxy); Y １ is -CH ２ - or -C(=O)-; Y ２ is -CH ２ -, -C(=O)-, -CHR ｙ２ａ -, -CH ２ -CH ２ -, -CH ２ -CHR ｙ２ｂ -, or -CHR ｙ２ａ -CH ２ -; R ｙ２ａ is selected from halo, cyano, methyl, methoxy, CF ３ , -OCF ３ or hydroxymethyl, and R ｙ２ｂ is selected from halo, cyano, hydroxy, methyl, methoxy, CF ３ , -OCF ３ or hydroxymethyl; A １ is selected from N, CH or CR １１ ; A ２ is selected from N, CH or CR １２ ; and A ３ is selected from N, CH or CR １３ ; and A ４ is selected from N, CH or CR １４ ; However, A １ , A ２ , A ３ or A ４ only one or two of them can be N; R １１ is cyano, halo, (1-2C)alkyl, (1-2C)alkoxy (wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy); or -(CHR ｚ ) ａ -Z １１ (wherein, R ｚ is hydrogen or methyl; a is 0 or 1; Z １１ is -OR １５ , -NR １６ R １７ , -C(O)NR １６ R １７ or -NR １８ C(O)R １９ wherein; R １５ is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｙ ), ｂ -(3-7C)cycloalkyl, -(CHR ｙ ), ｂ -phenyl, -(CHR ｙ ), ｂ -[4- to 8-membered heterocyclyl] or -(CHR ｙ ), ｂ -[5- or 6-membered heteroaryl], R ｙ is hydrogen or methyl, and b is 0 or 1; R １６ and R １７ are each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｗ ), ｃ -(3-7C)cycloalkyl, -(CHR ｗ ), ｃ -phenyl, -(CHR ｗ ), ｃ -[4- to 8-membered heterocyclyl] or -(CHR ｗ ), ｃ -[5- or 6-membered heteroaryl], R ｗ is hydrogen or methyl, and c is 0 or 1 or R １６ and R １７ are linked together with the nitrogen atoms attached thereto such that they form a 4- to 8-membered heterocyclic ring; R １８ is hydrogen or (1-2C) alkyl; R １９ is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｘ ) ｄ -(3-7C)cycloalkyl, -(CHR ｘ ) ｄ -phenyl, -(CHR ｘ ) ｄ -[4- to 8-membered heterocyclyl] or -(CHR ｘ ) ｄ -[5- or 6-membered heteroaryl]; R ｘ is hydrogen or methyl, and d is 0 or 1; R １５ 、R １６ 、R １７ 、R １８ or R １９ 、or R １６ and R １７ When any ring formed when R ａ is optionally substituted with one or more R R １２ has the following options: (i) R １１ is -(CHR ｚ ) ａ -Z １１ group, R １２ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy (wherein any (1-2C)alkyl or (1-2C)alkoxy may be optionally substituted by one or more halo or (1-2C)alkoxy), or (ii) R １１ is not a -(CHR ｚ ) ａ -Z １１ group, then R １２ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy (wherein any (1-2C)alkyl or (1-2C)alkoxy may be optionally substituted by one or more halo or (1-2C)alkoxy), or R １２ is -(CHR ｖ ) ｄ -Z １２ (wherein R ｖ is hydrogen or methyl; d is 0 or 1; Z １２ is -OR ２０ , -NR ２１ R ２２ , -C(O)NR ２１ R ２２ or -NR ２３ C(O)R ２４ ; R ２０ is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｕ ), ｅ -(3-7C)cycloalkyl, -(CHR ｕ ), ｅ -phenyl, -(CHR ｕ ), ｅ -[4- to 8-membered heterocyclyl] or -(CHR ｕ ), ｅ -[5- or 6-membered heteroaryl], R ｕ is hydrogen or methyl, and e is 0 or 1; R ２１ and R ２２ are each independently selected from hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a carbon-bonded 4- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｑ ), ｆ -(3-7C)cycloalkyl, -(CHR ｑ ), ｆ -phenyl, -(CHR ｑ ), ｆ -[4- to 8-membered heterocyclyl] or -(CHR ｑ ), ｆ -[5- or 6-membered heteroaryl], R ｑ is hydrogen or methyl, and f is 0 or 1; or R ２１ and R ２２ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 8-membered heterocyclic ring; R ２３ is hydrogen or (1-2C) alkyl; R ２４ is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｐ ), ｇ -(3-7C)cycloalkyl, -(CHR ｐ ), ｇ -phenyl, -(CHR ｐ ), ｇ -[4- to 8-membered heterocyclyl] or -(CHR ｐ ), ｇ -[5- or 6-membered heteroaryl], where R ｐ is hydrogen or methyl, and g is 0 or 1; R ２０ 、 R ２１ 、 R ２２ 、 R ２３ or R ２４ 、 or R ２１ and R ２２ When each of any rings formed when R ａ is optionally substituted with one or more R is selected from one of; R １３ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy (wherein any (1-2C)alkyl moiety is optionally substituted by one or more halo or (1-2C)alkoxy), or R １３ is -(CHR ｏ ) ｈ -Z １３ (wherein, R ｏ is hydrogen or methyl; h is 0 or 1; Z １２ is -OR ２５ -NR ２６ R ２７ -C(O)NR ２６ R ２７ or -NR ２８ C(O)R ２９ wherein; R ２５ is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or a 5- or 6-membered heteroaryl, -(CHR ｎ ), ｉ -(3-7C)cycloalkyl, -(CHR ｎ ), ｉ -phenyl, -(CHR ｎ ), ｉ -[4- to 8-membered heterocyclyl] or -(CHR ｎ ), ｉ -[5- or 6-membered heteroaryl], R ｎ is hydrogen or methyl, and i is 0 or 1; R ２６ and R ２７ are each independently selected from hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｍ ), ｊ -(3-7C)cycloalkyl, -(CHR ｍ ), ｊ -phenyl, -(CHR ｍ ), ｊ -[4- to 8-membered heterocyclyl] or -(CHR ｍ ), ｊ -[5- or 6-membered heteroaryl], R ｍ is hydrogen or methyl, and j is 0 or 1; or R ２６ and R ２７ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 8-membered heterocyclic ring; R ２８ is hydrogen or (1-2C) alkyl; R ２９ is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｌ ), ｋ -(3-7C)cycloalkyl, -(CHR ｌ ), ｋ -phenyl, -(CHR ｌ ), ｋ -[4- to 8-membered heterocyclyl] or -(CHR ｌ ), ｋ -[5- or 6-membered heteroaryl], R ｌ is hydrogen or methyl, and k is 0 or 1; R ２５ 、 R ２６ 、 R ２７ 、 R ２８ or R ２９ or R ２６ and R ２７ When any ring formed when R ａ is optionally substituted with one or more R R １４ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy (wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy), or R １４ is -(CHR ｋ ) ｍ -Z １４ (wherein, R ｋ is hydrogen or methyl; m is 0 or 1; Z １２ is -OR ３０ -NR ３１ R ３２ -C(O)NR ３１ R ３２ or -NR ３３ C(O)R ３４ wherein; R ３０ is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, 5- or 6-membered heteroaryl, -(CHR ｊ ), ｏ -(3-7C)cycloalkyl, -(CHR ｊ ), ｏ -[4- to 8-membered heterocyclyl] or -(CHR ｊ ), ｏ -[5- or 6-membered heteroaryl], R ｊ is hydrogen or methyl, o is 0 or 1; R ３１ and R ３２ are each independently selected from hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, a carbon-bonded 4- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｉ ), ｐ -(3-7C)cycloalkyl, -(CHR ｉ ), ｐ -[4- to 8-membered heterocyclyl] or -(CHR ｉ ), ｐ -[5- or 6-membered heteroaryl], R ｉ is hydrogen or methyl, and p is 0 or 1 or R ３１ and R ３２ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 8-membered heterocyclic ring; R ３３ is hydrogen or (1-2C) alkyl; R ３４ is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｈ ) ｑ -(3-7C)cycloalkyl, -(CHR ｈ ) ｑ -[4- to 8-membered heterocyclyl] or -(CHR ｈ ) ｑ -[5- or 6-membered heteroaryl], R ｈ is hydrogen or methyl, and q is 0 or 1; R ３０ 、 R ３１ 、 R ３２ 、 R ３３ or R ３４ 、 or R ３１ and R ３２ Any ring formed when R ａ is optionally substituted with one or more R Each R ａ is oxo, halogen, cyano, hydroxy, (1-4C)alkyl, or -L １ -X １ -Q １ group is independently selected from the group consisting of,[[]] L １ is absent or is (1-2C) alkylene; X １ is 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(R １４ ), —N(R １４ ), —C(O)—, —NR １４ —, —N(R １４ ), —C(O)—NR １４ —, —SO ２ N(R １４ ), or —N(R １４ ),SO ２ —, where R １４ is hydrogen or (1-2C) alkyl; Q １ is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl; Q １ When Q is (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl, Q １ is one or more Q ａ optionally substituted with, and each Q ａ is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (1-3C) haloalkyl, or (1-3C) haloalkoxy; R １２ or one of R １３ is optionally: -L-Q group or -L ｘ -X group, L is a linker; L ｘ is a linker; X is a functional group; Q is a detection moiety)] and a compound having the same or a pharmaceutically acceptable salt, hydrate or solvate thereof.

2. Formula I-I, I-II or I-III shown below: 【Chemical 3】 [wherein, R ６ , Y １ , Y ２ , A １ , A ２ , A ３ , A ４ , R １１ , R １２ , R １３ and R １４ are each as defined in claim 1], a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3. R ６ is (1-6C) alkyl, (3-6C) cycloalkyl, or a 4- to 6-membered heterocyclyl ring containing one heteroatom selected from N, O or S, Or a group having a structure according to formula (A) shown below: [Chemical Formula 4] [In the formula,[[]] R ７ is hydrogen or (1-3C) alkyl; n is 1 or 2; R ８ is (3-8C) cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more R ９ ; each R ９ is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (1-3C) haloalkyl, or (1-3C) haloalkoxy], the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4. R ６ is (1-4C)alkyl or a group having a structure represented by formula (A) shown below: 【Chemical Formula 5】 [In the formula,[[]] R ７ is hydrogen or (1-2C) alkyl; n is 1 or 2; R ８ is (3-6C) cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more R ９ ; each R ９ is independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C) alkyl, (1-2C) alkoxy, (1-2C) haloalkyl, or (1-2C) haloalkoxy], the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

5. R ６ is (1-3C)alkyl or a group having a structure according to formula (A) shown below: 【Chemical Formula 6】 [In the formula,[[]] R ７ is hydrogen or methyl; n is 1; R ８ is cyclohexyl, phenyl, a 6-membered heterocyclyl, or a 6-membered heteroaryl, each of which is optionally substituted with one or more R ９ groups; each R ９ is independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, or trifluoromethoxy], the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

6. R ６ is a group having a structure represented by formula (A) shown below: 【Chemical Formula 7】 [In the formula,[[]] R ７ is hydrogen or methyl; n is 1; R ８ is cyclohexyl, phenyl, 6-membered heterocyclyl, pyridyl, each of which is optionally substituted with one or more R ９ ; each R ９ is independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl, or trifluoromethoxy], the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

7. Y １ is -CH ２ -, the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

8. Y ２ is -CH ２ -, -CHR ｙ２ａ -, -CH ２ -CH ２ -, -CH ２ -CHR ｙ２ｂ -, or -CHR ｙ２ａ -CH ２ -; R ｙ２ａ is selected from halo, methyl or hydroxymethyl, R ｙ２ｂ is selected from halo, cyano, hydroxy, methyl, methoxy, CF ３ , -OCF ３ or hydroxymethyl, the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

9. Y ２ is -CH ２ - or -CH ２ -CH ２ -, the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

10. A １ 、 A ２ 、 A ３ or A ４ is one of the following options: (i) A １ is selected from N, CH or CR １１ ; A ２ is selected from N, CH or CR １２ ; and A ３ is selected from N, CH or CR １３ ; A ４ is selected from N, CH or CR １４ ; and However, A １ , A ２ , A ３ or A ４ only one of them can be N; (ii) A １ is CH or CR １１ and is selected from; A ２ is selected from N, CH or CR １２ ; A ３ is selected from N, CH or CR １３ ; A ４ is selected from N, CH or CR １４ ; and However, A ２ , A ３ or A ４ only one of them can be N; (iii) A １ is CR １１ and; A ２ is selected from N, CH or CR １２ ; A ３ is selected from N, CH or CR １３ ; and A ４ is selected from N, CH or CR １４ ; and However, A ２ , A ３ or A ４ only one of them can be N; (iv) A １ is CR １１ and; A ２ is selected from N or CH; A ３ is selected from N, CH or CR １３ ; and A ４ is selected from N or CH; However, A ２ , A ３ or A ４ only one of them can be N; (v) A １ is CR １１ and; A ２ is CH; A ３ is CH or CR １３ ; A ４ is CH; (vi) A １ is CR １１ and; A ２ is CH; A ３ is CH; A ４ is CH; (vii) A １ is CH; A ２ is CR １２ ; A ３ is CH; A ４ is CH; (viii) A １ is CH; A ２ is CH; A ３ is CR １３ ; A ４ is CH; The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, selected from one of them.

11. R １１ is (1-2C) alkyl optionally substituted by cyano, halo or one or more halo or (1-2C) alkoxy; or -(CHR ｚ ) ａ -Z １１ [wherein, R ｚ is hydrogen or methyl; a is 0 or 1; Z １１ is -OR １５ , -NR １６ R １７ , -C(O)NR １６ R １７ or -NR １８ C(O)R １９ and; R １５ is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｙ ), ｂ -(3-6C)cycloalkyl, -(CHR ｙ ), ｂ -phenyl, -(CHR ｙ ), ｂ -[4- to 6-membered heterocyclyl] or -(CHR ｙ ), ｂ -[5- or 6-membered heteroaryl], R ｙ is hydrogen or methyl, and b is 0 or 1; R １６ and R １７ are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, a 4- to 6-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｗ ), ｃ -(3-6C)cycloalkyl, -(CHR ｗ ), ｃ -phenyl, -(CHR ｗ ), ｃ -[4- to 6-membered heterocyclyl] or -(CHR ｗ ), ｃ -[5- or 6-membered heteroaryl], R ｗ is hydrogen or methyl, and c is 0 or 1 or R １６ and R １７ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 6-membered heterocyclic ring; R １８ is hydrogen or (1-2C) alkyl; R １９ is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｘ ) ｄ -(3-6C)cycloalkyl, -(CHR ｘ ) ｄ -phenyl, -(CHR ｘ ) ｄ -[4- to 6-membered heterocyclyl] or -(CHR ｘ ) ｄ -[5- or 6-membered heteroaryl]; R ｘ is hydrogen or methyl, and d is 0 or 1; R １５ 、 R １６ 、 R １７ 、 R １８ or R １９ 、 or R １６ and R １７ When each of any rings formed when R ａ is optionally substituted with one or more R R ａ is as defined in claim 1], the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

12. R １１ is cyano or -(CHR ｚ ) ａ -Z １１ [wherein, R ｚ is hydrogen or methyl; a is 0 or 1; Z １１ is -OR １５ , -NR １６ R １７ or -NR １８ C(O)R １９ and; R １５ is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｙ ) ｂ -(3-6C)cycloalkyl, -(CHR ｙ ) ｂ -phenyl, -(CHR ｙ ) ｂ -[4- to 6-membered heterocyclyl] or -(CHR ｙ ) ｂ -[5- or 6-membered heteroaryl], R ｙ is hydrogen or methyl, and b is 0 or 1; R １６ and R １７ are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-bonded 4- to 6-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｗ ), ｃ -(3-6C)cycloalkyl, -(CHR ｗ ), ｃ -phenyl, -(CHR ｗ ), ｃ -[4- to 6-membered heterocyclyl] or -(CHR ｗ ), ｃ -[5- or 6-membered heteroaryl], R ｗ is hydrogen or methyl, and c is 0 or 1 or R １６ and R １７ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 6-membered heterocyclic ring; R １８ is hydrogen or (1-2C) alkyl; R １９ is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, a 4- to 6-membered carbon-bonded heterocyclyl or 6-membered heteroaryl, or -(CHR ｘ ), ｄ -(3-6C)cycloalkyl; R ｘ is hydrogen or methyl, and d is 0 or 1; R １５ 、 R １６ 、 R １７ 、 R １８ or R １９ 、 or R １６ and R １７ When any ring formed by the connection of, or, or and is substituted in some cases by one or more R ａ ; R ａ is as defined in claim 1], the compound or a pharmaceutically acceptable salt, hydrate or solvate thereof according to claim 1.

13. R １１ is -(CHR ｚ ) ａ -Z １１ [wherein, R ｚ is hydrogen; a is 0 or 1; Z １１ is -NHR １７ and R １７ is; (i) A group of formula (A), (B), (C) or (D): 【Chemical 8】 [In the formula,[[]] W １ is OR ｗ１ａ or NR ｗ１ａ R ｗ１ｂ is selected from, and R ｗ１ａ and R ｗ１ｂ are each independently selected from hydrogen or (1-2C) alkyl; R Ｗ１Ｃ 、 R Ｗ１Ｄ and R Ｗ１Ｅ are each selected from hydrogen or methyl, or R Ｗ１Ｃ and R Ｗ１Ｄ or R Ｗ１Ｄ and R Ｗ１Ｅ are linked together with the carbon atoms to which they are attached such that they form a (4-6C) cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R ａ ; W ２ is selected from O, NR ｗ２ , S or S(O) ２ and R ｗ２ is selected from hydrogen, (1-4C)alkyl or (2-4C)alkanoyl; Each of formulas (B), (C) and (D) is optionally substituted by one or more R ａ ; R ａ is as defined in claim 1); (ii) Optionally selected from one of the following formulas (E) to (J), a cross-linked version of the above formulas (C) and (D): 【Chemical Formula 9】 (wherein, Y ４ is -CH ２ -, -CH ２ CH ２ is selected from -, and is selected from Each of formulas (E), (F), (G), (H) and (J) is optionally substituted by one or more R ａ ; and R ａ is as defined in claim 1); (iii) A group of the following formula (K), (L) or (M): 【Chemical Formula 10】 [In the formula,[[]] R Ｗ３ is selected from hydrogen or (1-2C) alkyl; W ３ 、 W ４ and W ５ is selected from N or CR ｗ４ and R ｗ４ is hydrogen, halo, (1-2C)alkyl or (1-2C)alkoxy; W ６ and W ７ One of them is N, and the other is CR ｗ５ where W ８ is N or CR ｗ５ and R ｗ５ is hydrogen, halo, (1-2C)alkyl or (1-2C)alkoxy; W ９ 、W １０ 、W １１ and W １２ is selected from N or CR ｗ６ , R ｗ６ is hydrogen, halo, (1-2C)alkyl or (1-2C)alkoxy; provided that only one or two of W ９ , W １０ , W １１ and W １２ are N) selected from, and] and a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

14. R １１ is -(CHR ｚ ) ａ -Z １１ [wherein, R ｚ is hydrogen; a is 0 or 1; Z １１ is -NHR １７ and R １７ is; (i) A group of formula (A), (B), (C) or (D): 【Chemical Formula 11】 [In the formula,[[]] W １ is OR ｗ１ａ or NR ｗ１ａ R ｗ１ｂ is selected from, and R ｗ１ａ and R ｗ１ｂ are each independently selected from hydrogen or (1-2C) alkyl; R Ｗ１Ｃ 、 R Ｗ１Ｄ and R Ｗ１Ｅ is selected from hydrogen, or R Ｗ１Ｃ and R Ｗ１Ｄ or R Ｗ１Ｄ and R Ｗ１Ｅ together with the carbon atoms to which they are attached are linked such that they form a (4-6C) cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R ａ ; W ２ is selected from O, NR ｗ２ or S(O) ２ and R ｗ２ is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; Each of formulas (B), (C), and (D) is optionally substituted by one or more R ａ ; and R ａ is as defined in claim 1); (ii) Optionally selected from one of the following formulas (E) to (J), a cross-linked version of the above formulas (C) and (D): 【Chemical 12】 (wherein Y ４ is selected from -CH ２ -, -CH ２ CH ２ -, and is selected from Each of formulas (E), (F), (G), (H) and (J) is optionally substituted by one or more R ａ ; and optionally R ａ is as defined in claim 1); (iii) A group of the following formula (K), (L) or (M): 【Chemical 13】 [In the formula,[[]] R Ｗ３ is selected from hydrogen or (1-2C) alkyl; W ３ , W ４ and W ５ is selected from N or CH; W ６ and W ７ One of them is N, the other is CH, and W ８ is either N or CH; W ９ 、W １０ 、W １１ and W １２ is selected from N or CR ｗ６ , and R ｗ６ is hydrogen, halo, (1-2C)alkyl or (1-2C)alkoxy; provided that only one of W ９ , W １０ , W １１ and W １２ is N) selected from, and] and a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

15. R １１ is -(CHR ｚ ) ａ -Z １１ [Wherein, R ｚ is hydrogen; a is 0 or 1; Z １１ is -NHR １７ and; R １７ is a group of formula (A), (B), (C) or (D): 【Chemical Formula 14】 [In the formula,[[]] W １ is OR ｗ１ａ or NR ｗ１ａ R ｗ１ｂ is selected from, and R ｗ１ａ and R ｗ１ｂ are each independently selected from hydrogen or (1-2C) alkyl; R Ｗ１Ｃ 、R Ｗ１Ｄ and R Ｗ１Ｅ are selected from hydrogen, or R Ｗ１Ｃ and R Ｗ１Ｄ or R Ｗ１Ｄ and R Ｗ１Ｅ together with the carbon atoms to which they are attached are linked such that they form a (4-6C) cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R ａ ; W ２ is selected from O, NR ｗ２ or S(O) ２ , and R ｗ２ is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of formulas (B), (C) and (D) is optionally substituted by one or more R ａ ; and R ａ is as defined in claim 1), a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

16. R １２ is the following option: (i) R １１ is -(CHR ｚ ) ａ -Z １１ group, R １２ is halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may be optionally substituted by one or more halo or (1-2C)alkoxy], or (ii) R １１ is not -(CHR ｚ ) ａ -Z １１ group, R １２ is halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy], or R １２ is -(CHR ｖ ) ｄ -Z １２ [wherein, R ｖ is hydrogen or methyl; d is 0 or 1; Z １２ is -OR ２０ , -NR ２１ R ２２ , -C(O)NR ２１ R ２２ or -NR ２３ C(O)R ２４ and; R ２０ is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｕ ), ｅ -(3-7C)cycloalkyl, -(CHR ｕ ), ｅ -phenyl, -(CHR ｕ ), ｅ -[4- to 8-membered heterocyclyl] or -(CHR ｕ ), ｅ -[5- or 6-membered heteroaryl], R ｕ is hydrogen, and e is 0 or 1; R ２１ and R ２２ are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｑ ), ｆ -(3-7C)cycloalkyl, -(CHR ｑ ), ｆ -phenyl, -(CHR ｑ ), ｆ -[4- to 8-membered heterocyclyl] or -(CHR ｑ ), ｆ -[5- or 6-membered heteroaryl], R ｑ is hydrogen or methyl, and f is 0 or 1; or R ２１ and R ２２ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 8-membered heterocyclic ring; R ２３ is hydrogen or methyl; R ２４ is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｐ ), ｇ -(3-7C)cycloalkyl, -(CHR ｐ ), ｇ -phenyl, -(CHR ｐ ), ｇ -[4- to 8-membered heterocyclyl] or -(CHR ｐ ), ｇ -[5- or 6-membered heteroaryl], R ｐ is hydrogen or methyl, and g is 0 or 1; R ２０ 、 R ２１ 、 R ２２ 、 R ２３ or R ２４ 、 or R ２１ and R ２２ When each of any rings formed when R ａ is optionally substituted with one or more R R ａ is as defined in claim 1]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, selected from one of them.

17. R １２ is the following option: (i) R １１ is -(CHR ｚ ) ａ -Z １１ group, R １２ is halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy], or (ii) R １１ is -(CHR ｚ ) ａ -Z １１ group, when R １２ is halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may be optionally substituted by one or more halo or (1-2C)alkoxy], or R １２ is -(CHR ｖ ) ｄ -Z １２ [wherein, R ｖ is hydrogen; d is 0 or 1; Z １２ is -OR ２０ , -NR ２１ R ２２ or -C(O)NR ２１ R ２２ and; R ２０ is (1-4C) alkyl; R ２１ and R ２２ are each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-bonded 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl; or R ２１ and R ２２ are linked together with the nitrogen atoms attached thereto such that they form a 4- to 8-membered heterocyclic ring; R ２０ 、 R ２１ or R ２２ 、 or R ２１ and R ２２ When each of any rings formed when R ａ is optionally substituted with one or more R R ａ is as defined in claim 1 The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, selected from one of the following.

18. R １２ is the following option: (i) R １１ is -(CHR ｚ ) ａ -Z １１ group, R １２ is halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy], or (ii) R １１ is not a -(CHR ｚ ) ａ -Z １１ group, R １２ is selected from halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy] The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, selected from one of the following.

19. R １３ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl moiety is optionally substituted by one or more halo or (1-2C)alkoxy], or R １３ is -(CHR ｏ ) ｈ -Z １３ [Wherein, R ｏ is hydrogen or methyl; h is 0 or 1; Z １２ is -OR ２５ , -NR ２６ R ２７ , -C(O)NR ２６ R ２７ or -NR ２８ C(O)R ２９ ; R ２５ is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｎ ), ｉ -(3-7C)cycloalkyl, -(CHR ｎ ), ｉ -phenyl, -(CHR ｎ ), ｉ -[4- to 8-membered heterocyclyl] or -(CHR ｎ ), ｉ -[5- or 6-membered heteroaryl], where R ｎ is hydrogen or methyl, and i is 0 or 1; R ２６ and R ２７ are each independently selected from hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or 5- or 6-membered heteroaryl, -(CHR ｍ ), ｊ -(3-7C)cycloalkyl, -(CHR ｍ ), ｊ -phenyl, -(CHR ｍ ), ｊ -[4- to 8-membered heterocyclyl] or -(CHR ｍ ), ｊ -[5- or 6-membered heteroaryl], R ｍ is hydrogen or methyl, and j is 0 or 1; or R ２６ and R ２７ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 8-membered heterocyclic ring; R ２８ is hydrogen or methyl; R ２９ is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, a 4- to 8-membered carbon-bonded heterocyclyl or a 5- or 6-membered heteroaryl, -(CHR ｌ ), ｋ -(3-7C)cycloalkyl, -(CHR ｌ ), ｋ -phenyl, -(CHR ｌ ), ｋ -[4- to 8-membered heterocyclyl] or -(CHR ｌ ), ｋ -[5- or 6-membered heteroaryl], where R ｌ is hydrogen or methyl, and k is 0 or 1; R ２５ 、 R ２６ 、 R ２７ or R ２９ or R ２６ and R ２７ When each of any rings formed when is linked, is optionally substituted with one or more R ａ ; in some cases R ａ is as defined in claim 1], the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

20. R １３ is selected from halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl moiety is optionally substituted by one or more halo or (1-2C)alkoxy], or R １３ is -(CHR ｏ ) ｈ -Z １３ [wherein, R ｏ is hydrogen or methyl; h is 0 or 1; Z １２ is -OR ２５ , -NR ２６ R ２７ , or -C(O)NR ２６ R ２７ ; R ２５ is (1-4C)alkyl, carbon-bonded 4- to 8-membered heterocyclyl, or -(CHR ｎ ), ｉ -[4- to 8-membered heterocyclyl], R ｎ is hydrogen or methyl, and i is 0 or 1; R ２６ and R ２７ are each independently selected from hydrogen, (1-6C)alkyl, carbon-bonded 4- to 8-membered heterocyclyl, or -(CHR ｍ ). ｊ -[4- to 8-membered heterocyclyl], R ｍ is hydrogen or methyl, and j is 0 or 1; or R ２６ and R ２７ are linked, together with the nitrogen atoms attached thereto, such that they form a 4- to 8-membered heterocyclic ring; R ２５ 、 R ２６ 、 R ２７ or R ２６ and R ２７ When each of any rings formed when is linked, is optionally substituted with one or more R ａ in some cases; R ａ is as defined in claim 1], a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

21. (i) R １４ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy [wherein any (1-2C)alkyl or (1-2C)alkoxy may optionally be substituted by one or more halo or (1-2C)alkoxy], or R １４ is -(CHR ｋ ) ｍ -Z １４ [wherein, R ｋ is hydrogen; m is 0 or 1; Z １２ is -OR ３０ , -NR ３１ R ３２ , -C(O)NR ３１ R ３２ or -NR ３３ C(O)R ３４ wherein; R ３０ is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR ｊ ) ｏ -(3-7C)cycloalkyl, or -(CHR ｊ ) ｏ -[4- to 8-membered heterocyclyl], R ｊ is hydrogen or methyl, and o is 0 or 1; R ３１ and R ３２ are each independently selected from hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, carbon-bonded 4- to 8-membered heterocyclyl, -(CHR ｉ ), ｐ -(3-7C)cycloalkyl, or -(CHR ｉ ), ｐ -[4- to 8-membered heterocyclyl], R ｉ is hydrogen or methyl, and p is 0 or 1 or R ３１ and R ３２ are linked together with the nitrogen atoms attached thereto so that they form a 4- to 8-membered heterocyclic ring; R ３３ is hydrogen or methyl; R ３４ is (1-6C)alkyl, (3-7C)cycloalkyl, a 4- to 8-membered heterocyclyl attached by a carbon bond, -(CHR ｈ ), ｑ -(3-7C)cycloalkyl, or -(CHR ｈ ), ｑ -[4- to 8-membered heterocyclyl], R ｈ is hydrogen or methyl, q is 0 or 1; R ３０ 、 R ３１ 、 R ３２ or R ３４ 、 or R ３１ and R ３２ Any ring formed when is connected is optionally substituted with one or more R ａ ; optionally in some cases R ａ is as defined in claim 1; or (ii) R １４ is selected from cyano, halo, (1-2C) alkyl, (1-2C) alkoxy [wherein any (1-2C) alkyl or (1-2C) alkoxy may optionally be substituted by one or more halo or (1-2C) alkoxy], the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

22. (i) Each R ａ is oxo, halogen, cyano, hydroxy, (1-4C)alkyl, or -L １ -X １ -Q １ group Independently selected from the group consisting of L １ is absent or is (1-2C) alkylene; X １ is 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(R １４ )—, —N(R １４ )—C(O)—, —NR １４ —, —SO ２ N(R １４ )—, or —N(R １４ )SO ２ —, where R １４ is hydrogen or (1-2C) alkyl; Q １ is selected from the group consisting of hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; Q １ When Q is (1-4C) alkyl or (3-6C) cycloalkyl, １ Q is one or more Q ａ which may be substituted in some cases, and each Q ａ is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (1-3C) haloalkyl, or (1-3C) haloalkoxy; (ii) Each R ａ is oxo, halogen, cyano, hydroxy, (1 to 2C) alkyl, or -L １ -X １ -Q １ group Independently selected from the group consisting of L １ is absent or is (1-2C) alkylene; X １ is 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(R １４ ), -N(R １４ ), -C(O)-, -NR １４ -, -SO ２ N(R １４ ), or -N(R １４ ),SO ２ -, and R １４ is hydrogen or (1-2C)alkyl; Q １ is selected from the group consisting of hydrogen, (1-2C) alkyl, or (3-6C) cycloalkyl; Q １ When Q is (1-2C) alkyl or (3-6C) cycloalkyl, １ Q is one or more Q ａ which may be substituted in some cases, and each Q ａ is independently selected from the group consisting of hydroxy, halogen, (1-2C) alkyl, (1-2C) alkoxy, (1-2C) haloalkyl, or (1-2C) haloalkoxy; (iii) each R ａ is oxo, halogen, cyano, hydroxy, (1-2C)alkyl, or -L １ -X １ -Q １ group Independently selected from the group consisting of L １ is absent or is (1-2C) alkylene; X １ is 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(R １４ )—, —N(R １４ )—C(O)—, or —NR １４から wherein R １４ is hydrogen or (1-2C)alkyl; Q １ is selected from the group consisting of hydrogen or (1-2C) alkyl; or Q １ When Q is (1-2C) alkyl, １ Q is one or more Q ａ which may optionally be substituted in some cases, and each Q ａ is independently selected from the group consisting of hydroxy, halogen, or (1-2C) alkoxy; (iv) each R ａ is oxo, halogen, cyano, hydroxy, (1-2C)alkyl, or -L １ -X １ -Q １ group Independently selected from the group consisting of L １ does not exist; X １ is absent or is selected from the group consisting of —O—, —C(O)—, —S(O) ０～２ —, —C(O)—N(R １４ )—, —N(R １４ )—C(O)—, or —NR １４から wherein R １４ is hydrogen or (1-2C) alkyl; Q １ is selected from the group consisting of hydrogen or (1-2C) alkyl; Q １ When Q is (1-2C) alkyl, １ Q is one or more Qs ａ which may be substituted in some cases, and each Q ａ is methoxy, the compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

23. The compound is as follows: (R)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydro-isoquinolin-2(1H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydro-isoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-(piperazin-1-ylmethyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-((methylamino)methyl)isoindolin-2-yl)methanone; 3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)oxy)cyclobutane-1-carbonitrile; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(1-(hydroxymethyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-4-yl)amino)isoindolin-2-yl)methanone; (2,4-Dihydroxy-6-methoxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-Ethoxy-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; 4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(pyrimidin-5-ylamino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((oxazol-4-ylmethyl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((1-methyl-1H-pyrazol-4-yl)amino)isoindolin-2-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (R)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; 4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-5-methylpyridin-2(1H)-one; (2-(Cyclopropylmethoxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Cyclohexylmethoxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Cyclohexylmethoxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((5,5-difluorotetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-2-yl)methyl)amino)isoindolin-2-yl)methanone; (4-((1H-Pyrazol-4-yl)amino)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((2-methyl-2H-1,2,3-triazol-4-yl)amino)isoindolin-2-yl)methanone; 1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)pyrrolidin-1-yl)ethan-1-one; (2-((4-Fluorobenzyl)oxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(((3,4-difluorobenzyl)oxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-(((4-methoxybenzyl)oxy)phenyl)(4-(((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(4-(((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(8-((2-methoxyethyl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(4-(((1-(oxetan-3-yl)ethyl)amino)isoindolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[6-[(dimethylamino)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[7-[(dimethylamino)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(4-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2 - Benzyloxy - 4,6 - dihydroxy - phenyl)-(4 - hydroxy - 3,4 - dihydro - 1H - isoquinolin - 2 - yl)methanone; (2-(Benzyloxy)-4,6 - dihydroxyphenyl)(4 - ((1 - methyl - 2 - oxabicyclo[2.1.1]hexan - 4 - yl)amino)isoindolin - 2 - yl)methanone; (4 - ((2 - Oxabicyclo[2.2.1]heptan - 4 - yl)amino)isoindolin - 2 - yl)(2 - (benzyloxy)-4,6 - dihydroxyphenyl)methanone; (2-(Benzyloxy)-4,6 - dihydroxyphenyl)(6 - methoxy - 8 - ((tetrahydrofuran - 3 - yl)amino)-3,4 - dihydroisoquinolin - 2(1H)-yl)methanone; (S)-(2,4 - Dihydroxy - 6 - (pyridin - 2 - ylmethoxy)phenyl)(8 - ((tetrahydrofuran - 3 - yl)amino)-3,4 - dihydroisoquinolin - 2(1H)-yl)methanone; (R)-(2,4 - Dihydroxy - 6 - (pyridin - 2 - ylmethoxy)phenyl)(8 - ((tetrahydrofuran - 3 - yl)amino)-3,4 - dihydroisoquinolin - 2(1H)-yl)methanone; (2,4 - Dihydroxy - 6 - (pyridin - 2 - ylmethoxy)phenyl)(8 - (oxetan - 3 - ylamino)-3,4 - dihydroisoquinolin - 2(1H)-yl)methanone; (S)-4 - ((2-(2,4 - Dihydroxy - 6 - (pyridin - 2 - ylmethoxy)benzoyl)-1,2,3,4 - tetrahydroisoquinolin - 8 - yl)amino)-1 - methylpyrrolidin - 2 - one; (R)-4 - ((2-(2,4 - Dihydroxy - 6 - (pyridin - 2 - ylmethoxy)benzoyl)-1,2,3,4 - tetrahydroisoquinolin - 8 - yl)amino)-1 - methylpyrrolidin - 2 - one; (R)-(2-(Benzyloxy)-4,6 - dihydroxyphenyl)(6 - (2 - methoxyethoxy)-8 - ((tetrahydrofuran - 3 - yl)amino)-3,4 - dihydroisoquinolin - 2(1H)-yl)methanone; 4 - ((2-(2-(Benzyloxy)-4,6 - dihydroxybenzoyl)-1,2,3,4 - tetrahydroisoquinolin - 8 - yl)amino)-1 - methylpyrrolidin - 2 - one; 4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-3-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-(((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyrrolidin-1-yl)ethan-1-one; (R)-1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyrrolidin-1-yl)ethan-1-one; (S)-1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)piperidin-1-yl)ethan-1-one; (R)-1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)piperidin-1-yl)ethan-1-one; 1-(4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)piperidin-1-yl)ethan-1-one; 5-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpiperidin-2-one; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(pyrimidin-5-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-methoxy-8-(((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)benzamide; 4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)benzamide; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(cyclopentylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((1-methylpiperidin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((1-methylpyrrolidin-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((methylamino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((((tetrahydrofuran-3-yl)amino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((((oxetan-3-ylamino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((((3-methyloxetan-3-yl)amino)methyl)isoindolin-2-yl)methanone; (4-(Aminomethyl)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone hydrochloride; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(7-((oxetan-3-ylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(7-((((tetrahydrofuran-3-yl)amino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-N-methylisoindoline-5-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-N,N-dimethylisoindoline-5-carboxamide; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone; (4-(Azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; 2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-4-carbonitrile; 1-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile; (4-Aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; N-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)acetamide; N-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)methyl)acetamide; (2,4-Dihydroxy-6-(pyridin-3-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-Dihydroxy-6-(pyridin-4-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-Dihydroxy-6-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2,4-Dihydroxy-6-(pyridazin-3-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; 8-Amino-3,4-dihydroisoquinolin-2(1H)-yl(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone; N-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)acetamide; N-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)tetrahydrofuran-3-carboxamide; t-Butyl (5-(4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamate; (5-(((4-(5-Aminopentyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxyphenyl)methanone hydrochloride; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-((((tetrahydrofuran-3-yl)methyl)amino)isoindolin-2-yl)methanone; 3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-N,N-dimethylpyrrolidine-1-carboxamide; 4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpiperidin-2-one; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(4-(((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(7-fluoro-8-(((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(pyridin-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(pyrazin-2-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(pyridazin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(((4-methylpiperazin-1-yl)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(((4-methylpiperazin-1-yl)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((4-methylpyrimidin-5-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2,4-dihydroxy-6-((3-methylbenzyl)oxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(((dimethylamino)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(((dimethylamino)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinolin-6-yl)(4-methylpiperazin-1-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-N,N-dimethyl-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide; (S)-2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-N,N-dimethyl-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide; (R)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl)amino)-1-methylpyridin-2(1H)-one; 5-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyridin-2(1H)-one; 5-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyridin-2(1H)-one; (R)-4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one; (S)-4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one; (R)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(Cyclohexylmethoxy)-4,6-dihydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2-(Cyclopropylmethoxy)-4,6-dihydroxyphenyl)(6-(2-methoxyethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (R)-(2,4-Dihydroxy-6-(pyridin-2-ylmethoxy)phenyl)(6-(2-methoxyethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(methyl(tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)-(5-(((oxetan-3-ylamino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-((((tetrahydrofuran-3-yl)amino)methyl)isoindolin-2-yl)methanone; (3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)azetidin-1-yl)ethan-1-one; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(8-(((4-methoxytetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 1-(3-((2-(2-(Benzyloxy)-4,6-bis(methoxymethoxy)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)(methyl)amino)azetidin-1-yl)ethan-1-one; (S)-1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)(methyl)amino)pyrrolidin-1-yl)-4-methoxybutan-1-one; (S)-1-(3-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)pyrrolidin-1-yl)-4-methoxybutan-1-one; 5-(((5-(4-((2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethylimino)-3H-xanthen-9-yl)benzoate; t-Butyl (5-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)carbamate; N-(5-Aminopentyl)-2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamide hydrochloride; 5-(((5-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethylimino)-3H-xanthen-9-yl)benzoate; 1-(6-((5-(2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)isoindoline-5-carboxamido)pentyl)amino)-6-oxohexyl)-3,3-dimethyl-2-((1E,3E)-5-((E)-1,3,3-trimethylindolin-2-ylidene)penta-1,3-dien-1-yl)-3H-indole-1-ium formate; N-(5-((4-((2-(2-(benzyloxy)-4,6-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyloxy)-3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-3-yl)propeneamide; and 2-(2-(Benzyloxy)-4,6-dihydroxybenzoyl)-N-(5-(3-(5,5-difluoro-7-(1H-pyrrol-2-yl)-5H-4λ ４ ,5λ ４ -dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-3-yl)propanamide)pentyl)isoindoline-5-carboxamide The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, selected from any one of the above.

24. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, mixed with a pharmaceutically acceptable diluent or carrier.

25. (i) a therapy; (ii) the treatment of cancer; (iii) the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with another anti-cancer agent (e.g., a chemotherapeutic agent, an immune checkpoint inhibitor, an immunostimulant or a DNA damage repair modulator); (iv) the treatment of a triplet repeat disorder The compound or a pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 23, or the pharmaceutical composition according to claim 24, for use in the treatment as defined above.

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