Inhibitors of MLH1 and / or PMS2 for cancer treatment

Abstract

The present invention relates to compounds of formula (I) that target MLH1 and / or PMS2 proteins, which are components of the DNA mismatch repair (MMR) process: wherein R 1 , R 2 , R 3 , R 4 , R 6 and R 10 are each as defined herein. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative diseases such as cancer and other diseases or conditions involving MLH1 and / or PMS2 activity.

Description

Technical Field

[0001] The present invention relates to certain compounds that are inhibitors of the activity of MLH1 and / or PMS2 proteins. The compounds of the present invention can be used to treat diseases or conditions that are mediated, at least in part, by inappropriate MLH1 and PMS2 activities, such as cancer. The present invention also relates to the use of these compounds as medicaments, methods for preparing them, and pharmaceutical compositions containing them. Background Art

[0002] Cancer is caused by altered cell proliferation. In recent decades, what exactly causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intensive research. This research has led to the identification of molecular targets associated with key pathways that cause such malignancies.

[0003] Mismatch repair (MMR) is a highly conserved DNA repair pathway that plays a major role in DNA replication, repair, and recombination, as well as in eukaryotic meiosis and mammalian immunoglobulin maturation / diversification. MMR promotes genomic stability in all organisms by correcting occasional DNA base mismatches and insertion / deletion (indel) loops that occur during normal DNA replication. Base pair mismatches occur when incorrect nucleotides are inserted into the newly synthesized DNA strand and escape the proofreading function of DNA polymerase. Indel loops typically occur in microsatellites, which are highly polymorphic short repeat DNA sequences distributed throughout the genomes of prokaryotes and eukaryotes. Typically, on microsatellites, the template and primer strands are prone to slippage (dissociation and reannealing) during replication, which can generate loop structures and inconsistent numbers of repeat units between the template and the newly synthesized strand.

[0004] DNA mismatch repair is a bidirectional excision and resynthesis system that moves from a defined strand break at the 3′- or 5′-end towards the mismatch; the excision tract just extends past 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 where distant DNA strand breakage begins; 3) excision of the incorrect DNA strand, and 4) resynthesis of the excised gap using the remaining DNA strand as a template [1]. MMR is a highly conserved biological pathway. In humans, mismatch recognition by hMutSα (MSH2-MSH6) or hMutSβ (MSH2-MSH3) initiates the MMR pathway. Binding of hMutSα or hMutSβ to the mismatch site leads to recruitment of MutLα (MLH1-PMS2) to form a ternary complex, whose protein-protein and protein-DNA interactions are regulated by the ATP / ADP cofactor. Proliferating cell nuclear antigen (PCNA) may play a role in recruiting MMR proteins to the vicinity of the replication fork [1]. PCNA can also activate the latent endonuclease activity in 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). When DNA resynthesis is complete, the remaining gap is ligated by DNA ligase to restore duplex integrity [2]. Consistent with this function, MMR is an important tumor suppressor pathway and is absent in up to 40% of sporadic cancers. In addition, individuals with germline mutations in MMR genes develop cancer susceptibility conditions.

[0005] Lynch syndrome (LS, previously known as hereditary non-polyposis colorectal cancer) is the most common cause of hereditary colorectal cancer (CRC), accounting for 2-5% of all cases. LS also presents an increased risk of malignancies at certain extracolonic sites, such as the endometrium, ovary, stomach, and small intestine, etc. [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 of one wild-type allele is sufficient to produce adequate MMR activity until a second hit inactivates the wild-type allele, resulting in MMR deficiency.

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

[0007] MMR-deficient cancers are typically and characteristically associated with a higher rate of DNA mutation accumulation than normal cells and other tumors; for example, CMMRD tumors typically have an ultra-high mutational phenotype (>250 substitution mutations / Mb) [4]. MMR deficiency also leads to an increase or decrease in the length of microsatellite repeats, known as microsatellite instability (MSI). Cancers with more than 40% microsatellite variation (two or more of five microsatellite markers routinely tested being positive) are described as high-frequency MSI (MSI-H). Tumors without MSI are microsatellite stable (MSS), while those with less than 40% microsatellite variation (one of the five markers showing microsatellite instability) are low-frequency MSI (MSI-L) [5]. MSI analysis is a widely used diagnostic biomarker for MMR-deficient tumors, and the MSI status is associated with a high prevalence of frameshift (FS) mutations occurring due to insertions / deletions within microsatellites. In addition to altering the downstream function of the protein, FS also creates a new amino acid sequence that serves as a substrate for antigen processing and presentation [6], stimulating the activation of the "helper" functions of CD8+ T cells (class I) and CD4+ T cells (class II).

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

[10] .

[0009] It is now generally recognized that a clinical response to immune checkpoint inhibitors requires the presence of tumor neoantigens and the infiltration of T cells that recognize these neoantigens. Higher neoantigen loads in patients with melanoma and non-small cell lung cancer are associated with responses to CTLA-4 and PD-1 blockade [11, 12, 13]. The number of neoantigens is related to TMB, and several large studies have confirmed that high TMB is associated with enhanced checkpoint inhibitor responses and improved overall survival in certain 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 through MLH1 silencing increases TMB and results in a "dynamic mutational spectrum", leading to the continuous renewal of neoantigens in vitro and in vivo. In a mouse model, this triggers immune surveillance and results in the control of tumor growth, especially in combination with immune checkpoint inhibition

[20] . Similar results were observed after MSH2 silencing

[21] .

[0011] Guan et al. and Lu et al. reported that MLH1 deficiency leads to the release of cytoplasmic DNA, activation of the cGAS-STING pathway, and IFN-β production. Guan et al. demonstrated that MLH1 deletion leads to overexpression of DNA, depletion of RPA, chromosomal instability, and cytoplasmic DNA accumulation. Lu et al. reported that the sensing of cytoplasmic DNA by the cGAS STING pathway contributes to the clinical benefit of immunotherapy in patients with MMR-deficient tumors. These reports suggest that the elimination of MMR activity may trigger beneficial immune activation by activating the cGAS-STING pathway.

[0012] Therefore, there is a strong biological and clinical rationale highlighting the need for inhibitors that target the MLH1 and / or PMS2 proteins, which are key components of DNA MMR for reawakening the anti-tumor immune response.

[0013] Accordingly, the present invention provides methods of treating cancer by using small molecules as single agents and in combination with immunotherapeutic agents, other DNA damage response pathway modulators, and / or standard-of-care chemotherapeutic agents to bind and modulate the function of the DNA MMR components MLH1 and / or PMS2.

[0014] Outside the cancer field, trinucleotide repeat disorders include over 30 human neurodegenerative and neuromuscular genetic diseases, such as Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar ataxia (SCA). These diseases are characterized by the amplification of simple repeat sequences in genomic DNA. These unstable repeat sequences are typically found in different regions of several genes, and their amplification can cause disease through multiple loss-of-function and gain-of-function pathways, such as by interfering with the expression or properties of gene products, or by affecting splicing or antisense regulation. Several mechanisms, including errors during DNA replication, meiotic recombination, transcription, DNA repair, and chromatin remodeling processes, are thought to be responsible for repeat instability, which can occur at different stages of the cell cycle. There is evidence that a functional MMR pathway is required to maintain the stability of microsatellite sequences: for example, compared to Msh2+ / + HD exon 1 mice, Msh2- / - transgenic mice carrying a human HD exon 1 copy (containing the CAG repeat) showed a reduction in the introduced (CAG)n repeat amplification

[22] .

[0015] Therefore, compounds that target the MLH1 and / or PMS2 components of the DNA MMR process are also needed to treat trinucleotide repeat diseases. The present invention was designed in view of the foregoing. The present invention was designed in view of the foregoing.

[0016] References

[0017] 1. Martin-Lopez, J.V. and R. Fishel, The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome. Fam Cancer, 2013. 12(2): p. 159-68.

[0018] 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.

[0019] 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.

[0020] 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

[0021] 5. Sehgal, R., et al., Lynch syndrome: an updated review. Genes (Basel), 2014. 5(3): p. 497-507

[0022] 6. Willis, J. A., et al., Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate. Clin Cancer Res, 2019.

[0023] 7. Gubin, M. M. and R. D. Schreiber, CANCER. The odds of immunotherapy success. Science, 2015. 350(6257): p. 158-9.

[0024] 8. Kloor, M. and M. von Knebel Doeberitz, The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer, 2016. 2(3): p. 121-133.

[0025] 9. Giannakis, M., et al., Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep, 2016. 17(4): p. 1206.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 20. Germano, G., et al., Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature, 2017. 552(7683): p. 116 - 120.

[0037] 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.

[0038] 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.

[0039] 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,

[0040] 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

[0041] 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.

[0042] According to another 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, and a pharmaceutically acceptable diluent or carrier.

[0043] According to another aspect of the present invention, there is provided a method for inhibiting MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activities) in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0044] According to another aspect of the present invention, there is provided a method for treating a disease or disorder in a patient in need thereof, wherein MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activities) is involved, the method comprising administering to the 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.

[0045] According to another aspect of the present invention, there is provided a method for treating a proliferative disease in a patient in need thereof, the method comprising administering to the 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.

[0046] According to another aspect of the present invention, there is provided a method of treating cancer in a patient in need thereof, the method comprising administering to the 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.

[0047] According to another 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 ataxia (SCA)) in a patient in need thereof, the method comprising administering to the 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.

[0048] According to another 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.

[0049] According to another 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.

[0050] According to another 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 treating a proliferative disease.

[0051] According to another 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 cancer. In a specific embodiment, the cancer is a human cancer.

[0052] According to another 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 a specific embodiment, 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 ataxia (SCA).

[0053] According to another 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).

[0054] According to another aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein for the treatment of a disease or disorder involving MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities).

[0055] According to another aspect of the present invention, there is provided the use of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the preparation of a medicament for the treatment of a proliferative disease.

[0056] According to another aspect of the present invention, there is provided the use of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the preparation of a medicament for the treatment of cancer.

[0057] According to another aspect of the present invention, there is provided the use of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the preparation of a medicament for the treatment of a trinucleotide disorder. In a specific embodiment, the trinucleotide 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 ataxia (SCA).

[0058] According to another aspect of the present invention, there is provided the use of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the preparation of a medicament for inhibiting MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities).

[0059] According to another aspect of the present invention, there is provided the use of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the preparation of a medicament for the treatment of a disease or disorder involving MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities).

[0060] According to another aspect of the present invention, there is provided a method for preparing a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.

[0061] According to another aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof which can be obtained by the method for preparing the compound defined herein, or by the method for preparing the compound defined herein, or directly obtained by the method for preparing the compound defined herein.

[0062] According to another aspect of the present invention, there is provided a novel intermediate as defined herein which is suitable for any of the synthetic methods listed herein.

[0063] In the above aspects of the present invention, the proliferative disease is suitably cancer, and the cancer is suitably human cancer. In particular, the compounds of the present invention will be used to treat 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, appendiceal cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, biliary tract cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney syndrome, central nervous system tumor, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor - GIST, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor (e.g., tumors of the gastrointestinal tract, lung or pancreas), neurofibromatosis type 1 and type 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi sarcoma 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, Waldenstrom macroglobulinemia, Werner syndrome, Wilms tumor and xeroderma pigmentosum).Particular cancers of interest include blood cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt 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, gastroesophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, central nervous system cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0064] Features related to one aspect of the present invention, including optional, suitable, and preferred features, can also be features related to any other aspect of the present invention, including optional, suitable, and preferred features.

[0065] Detailed description of the present invention

[0066] Definitions

[0067] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0068] It should be understood that reference to "treatment" or "treating" includes prevention as well as alleviating the established symptoms of a condition. Thus, "treatment" or "treating" a condition, disorder, or disease includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or disease in a human who may have or be susceptible to the condition, disorder, or disease but has not yet experienced or manifested clinical or subclinical symptoms of the condition, disorder, or disease, (2) inhibiting the condition, disorder, or disease, i.e., preventing, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or inhibiting at least one of its clinical or subclinical symptoms, or (3) alleviating or reducing at least one of the disease or its clinical or subclinical symptoms, i.e., causing regression of the condition, disorder, or disease.

[0069] A "therapeutically effective amount" means an amount of a compound sufficient to effect the treatment of a disease when administered to a mammal for treating the disease. The "therapeutically effective amount" will vary depending on the compound, the disease of the mammal being treated and its severity, as well as age, weight, etc. It should be understood that in, for example, humans or other mammals, the 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 an equivalent foreign regulatory agency for a particular disease and the subject being treated. It should be understood that determining the appropriate dosage form, dose, and route of administration is within the ordinary skill level in the pharmaceutical and medical arts.

[0070] As used herein alone or in combination with one or more other terms, "subject" and "patient" refer to an animal (e.g., a mammal), particularly a human. Suitably, a "subject" and a "patient" can be a non-human animal (e.g., a domestic animal and a domestic pet) or a human.

[0071] As used herein alone or in combination with one or more other terms, "pharmaceutically acceptable" refers to a substance that is generally chemically and / or physically compatible with other ingredients (e.g., with respect to a formulation), and / or is generally physiologically compatible with its recipient (e.g., a subject).

[0072] In the present specification, the term "alkyl" includes straight-chain and branched-chain alkyls. When referring to a single alkyl such as "propyl", it is only for the straight-chain form, and when referring to a single branched-chain alkyl such as "isopropyl", it is only for the branched-chain form. For example, "(1-6C) alkyl" includes (1-4C) alkyl, (1-3C) alkyl, propyl, isopropyl, and tert-butyl.

[0073] The term "(m-nC)" or "(m-nC) group", used alone or as a prefix, refers to any group having from m to n carbon atoms.

[0074] "Alkylene" is an alkyl that is located between two other chemical groups and is used to link them. Thus, "(1-6C) alkylene" refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene (-CH2-), ethylene isomers (–CH(CH3)– and –CH2CH2–), propylene isomers (–CH(CH3)CH2–, –CH(CH2CH3)–, –C(CH3)2– and –CH2CH2CH2–), pentylene (-CH2CH2CH2CH2CH2-), etc.

[0075] The term "alkenyl" refers to straight-chain and branched-chain alkyls containing 2 or more carbon atoms, wherein there is at least one carbon-carbon double bond in the group. Examples of alkenyls include vinyl, propenyl, and but-2,3-enyl, and include all possible geometric (E / Z) isomers.

[0076] The term "alkynyl" refers to straight-chain and branched-chain alkyls containing 2 or more carbon atoms, wherein there is at least one carbon-carbon triple bond in the group. Examples of alkynyls include ethynyl and propynyl.

[0077] "(m-nC) cycloalkyl" refers to a saturated hydrocarbon cyclic system containing from m to n carbon atoms. Exemplary cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicyclo[2.2.1]heptyl.

[0078] The term "alkoxy" refers to O-linked straight-chain and branched-chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0079] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen (e.g., fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2, and -CF3.

[0080] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine, more preferably fluorine and chlorine.

[0081] The term "carbocyclic group", "carbocyclic", or "carbocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system. The monocyclic carbocycle contains about 3 to 12 (suitably 3 to 7) ring atoms. The bicyclic carbocycle contains 6 to 17 member atoms in the ring, preferably 7 to 12 member atoms. The bicyclic carbocycle can be a fused ring, spiro ring, or bridged ring system. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, and spiro[3.3]heptyl.

[0082] The terms "heterocyclic group", "heterocyclic", or "heterocycle" refer to non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic systems. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms, having 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. Bicyclic heterocycles can be fused ring, spiro ring, 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 hexahydrothiophene. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolanyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, it also includes sulfur-containing heterocycles containing SO or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholine 1,1-dioxide. Heterocycles can contain 1 or 2 oxo(=O) or thioxo(=S) substituents. Suitable values of heterocyclic groups with 1 or 2 oxo(=O) or thioxo(=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl. Specific heterocyclic groups are saturated monocyclic 3-7 membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothiophene 1,1-dioxide, thiomorpholinyl, thiomorpholine 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As those skilled in the art will understand, any heterocycle can be attached to another group through any suitable atom, such as through a carbon or nitrogen atom. However, as used herein, piperidinyl or morpholino refers to piperidin-1-yl or morpholin-4-yl ring attached through the ring nitrogen.

[0083] "Bridged ring system" means a cyclic system in which two rings share more than two atoms. See, for example, Jerry March's "Advanced Organic Chemistry", 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclic ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinuclidine.

[0084] "Spirobicyclic system" means two cyclic systems sharing a common spiro carbon atom, i.e., a heterocycle is linked to another carbocyclic or heterocyclic ring through a common spiro carbon atom. Examples of spiro 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.

[0085] As used herein, either alone or in combination with one or more other terms, "aromatic" means monocyclic and polycyclic systems containing 4n + 2 π electrons, where n is an integer. Aromatic is understood to mean and include cyclic systems containing only carbon atoms (i.e., "aryl") as well as cyclic systems containing at least one heteroatom selected from N, O, or S (i.e., "heteroaromatic" or "heteroaryl"). Aromatic cyclic systems may be substituted or unsubstituted.

[0086] As used herein, either alone or in combination with one or more other terms, "non-aromatic" means a monocyclic or polycyclic system having at least one double bond that is not part of an extended conjugated π system. As used herein, non-aromatic means and includes cyclic systems containing only carbon atoms as well as cyclic systems containing at least one heteroatom selected from N, O, or S. Non-aromatic cyclic systems may be substituted or unsubstituted.

[0087] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring containing one or more (e.g., 1-4, especially 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes monovalent and divalent species. Examples of heteroaryl are monocyclic and bicyclic groups containing 5-12 ring members, more usually 5-10 ring members. Heteroaryl can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by fused 5- and 6-membered rings or two fused 6-membered rings. Each ring can contain up to about 4 heteroatoms, usually selected from nitrogen, sulfur and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl, including any amino substituents on the ring, will be less than five.

[0088] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazolyl, benzofuryl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyridazinyl, thieno[2,3-b]furyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d]-oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also includes a partially aromatic bicyclic or polycyclic system in which at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuryl, 2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuryl, 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.

[0089] Examples of five - membered heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0090] Examples of six - membered heteroaryls include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0091] The bicyclic heteroaryl can be, for example, a group selected from:

[0092] A benzene ring fused to a 5 - or 6 - membered ring containing 1, 2, or 3 ring heteroatoms;

[0093] A pyridine ring fused to a 5 - or 6 - membered ring containing 1, 2, or 3 ring heteroatoms;

[0094] A pyrimidine ring fused to a 5 - or 6 - membered ring containing 1, 2, or 2 ring heteroatoms;

[0095] A pyrrole ring fused to a 5 - or 6 - membered ring containing 1, 2, or 3 ring heteroatoms;

[0096] A pyrazole ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0097] A pyrazine ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0098] An imidazole ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0099] An oxazole ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0100] An isoxazole ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0101] A thiazole ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0102] An isothiazole ring fused to a 5 - or 6 - membered ring containing 1 or 2 ring heteroatoms;

[0103] A thiophene ring fused to a 5 - or 6 - membered ring containing 1, 2, or 3 ring heteroatoms;

[0104] A furan ring fused to a 5 - or 6 - membered ring containing 1, 2, or 3 ring heteroatoms;

[0105] A cyclohexyl ring fused to a 5 - or 6 - membered heteroaryl ring containing 1, 2, or 3 ring heteroatoms; and

[0106] A cyclopentyl ring fused to a 5 - or 6 - membered heteroaryl ring containing 1, 2, or 3 ring heteroatoms.

[0107] Specific examples of bicyclic heteroaryls containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guanyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl.

[0108] Specific examples of bicyclic heteroaryls containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanonyl, isochromanonyl, benzodioxanyl, quinolinyl, benzoxazinyl, benzodiazinyl, pyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0109] 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 include, but are not limited to, phenyl, biphenyl, naphthyl, etc. In a particular embodiment, the aryl is phenyl.

[0110] This specification also uses several compound terms to describe groups containing more than one functionality. For example, (3-6C) cycloalkyl(m-nC)alkyl includes (m-nC)alkyl substituted with (3-6C) cycloalkyl.

[0111] The term "optionally substituted" refers to substituted and unsubstituted groups, structures, or molecules. The term "wherein one / any of the CH, CH2, CH3 groups or heteroatom (i.e., NH) in the R 1 group is optionally substituted" suitably means that (any) one hydrogen group in the R 1 group is substituted with the relevant specified group.

[0112] When the optional substituent is selected from "one or more" groups, it should be understood that this definition includes all substituents selected from one particular group or substituents selected from two or more particular groups. In some embodiments, one or more means one, two, or three. In another embodiment, one or more means one or two. In a particular embodiment, one or more means one.

[0113] The phrase "the compounds of the present invention" refers to those compounds disclosed herein, including both general and specific ones.

[0114] "About", when used in conjunction with a measurable value such as an amount or a period of time, is intended to include a reasonable variation of that value, e.g., taking into account experimental error in the measurement of the value.

[0115] Compounds

[0116] On the one hand, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, as follows:

[0117]

[0118] wherein

[0119] R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, halogen and (1-4C) alkoxy, provided that at least one of R 1 and R 3 is hydroxy;

[0120] R 2 is hydrogen or fluorine;

[0121] R 4 is selected from the group consisting of hydrogen, halogen, (1-6C) alkyl, (3-6C) cycloalkyl and (3-6C) cycloalkyl(1-2C) alkyl, wherein the (1-6C) alkyl is optionally substituted with one or more R 5a and the (3-6C) cycloalkyl and (3-6C) cycloalkyl(1-2C) alkyl are optionally substituted with one or more R 5b ; wherein each R 5a is independently selected from halogen or (1-4C) alkoxy, and each R 5b is independently selected from the group consisting of halogen, (1-4C) alkyl and (1-4C) alkoxy;

[0122] R 6 is (1-6C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkyl(1-2C) alkyl or a 4-7 membered heterocyclic ring containing a heteroatom selected from N, O or S, or a group having a structure of formula (A) as follows:

[0123]

[0124] wherein

[0125] R 7 is hydrogen or (1-3C) alkyl;

[0126] n is 1 or 2;

[0127] R 8 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 9 ; wherein each R 9 is independently selected from hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (2-3C) alkenyl or (2-3C) alkynyl;

[0128] R 10 is -NR 11 R 12 wherein R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form a 5 - 7 - membered monocyclic heterocycle which is fused to a 5 - 6 - membered monocyclic heteroaromatic ring or a benzene ring to form an 8 - 11 - membered bicyclic heteroaromatic ring;

[0129] wherein any one or more of the rings present in R 10 are independently optionally substituted by one or more R 13 substituents;

[0130] each R 13 is independently selected from the group consisting of halogen, cyano, oxo, epoxy and the group

[0131] -L 1 -X 1 -Q 1 wherein:

[0132] wherein:

[0133] L 1 is absent or is a (1 - 3C) alkylene;

[0134] 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 -, -SO2N(R 14 ) - or -N(R 14 )SO2 - wherein R 14 is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1 - 4C) alkyl, (2 - 4C) alkenyl and (2 - 4C) alkynyl each time it appears, wherein any (1 - 4C) alkyl, (2 - 4C) alkenyl or (2 - 4C) alkynyl in R 14 is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy;

[0135] Q 1Selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heterocyclic group, heterocyclic group(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl, wherein Q 1 Any of the (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heterocyclic group, heterocyclic group(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)alkyl in 1 is optionally substituted by one or more groups R 15 ; and

[0136] Each R 15 is independently selected from the group consisting of hydroxy, cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy, -NR 15a R 15b , -C(O)-R 15a , -C(O)-OR 15a , -O-C(O)-R 15a , -C(O)-NR 15a R 15b , -N(R 15b )C(O)-R 15a , -S(O) 0-2 R 15a , -S(O)2NR 15a R 15b and -N(R 15b )-S(O)2R 15a ; wherein R 15a and R 15b are each independently hydrogen or (1-3C)alkyl, and any (1-3C)alkyl moiety present in the R 15a or R 15b group is optionally further substituted by one or more substituents independently selected from hydroxy, cyano, halogen, -OR 15c , -NR 15c R 15d and -C(O)-R 15c ; wherein R 15c and R 15d are both independently selected from hydrogen and (1-2C)alkyl.

[0137] On the other hand, the present invention relates to a compound of structural formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, as follows:

[0138]

[0139] wherein

[0140] R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, halogen and (1-4C) alkoxy, provided that at least one of R 1 and R 3 is hydroxy;

[0141] R 2 is hydrogen or fluoro;

[0142] R 4 is selected from the group consisting of hydrogen, halogen, (1-6C) alkyl, (3-6C) cycloalkyl and (3-6C) cycloalkyl(1-2C) alkyl, wherein said (1-6C) alkyl is optionally substituted by one or more R 5a and said (3-6C) cycloalkyl and (3-6C) cycloalkyl(1-2C) alkyl are optionally substituted by one or more R 5b ; wherein each R 5a is independently selected from halogen or (1-4C) alkoxy, and each R 5b is independently selected from the group consisting of halogen, (1-4C) alkyl and (1-4C) alkoxy;

[0143] R 6 is (3-8C) cycloalkyl, (3-8C) cycloalkyl(1-2C) alkyl or a 4-7 membered heterocyclic ring containing a heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below:

[0144]

[0145] wherein

[0146] R 7 is hydrogen or (1-3C) alkyl;

[0147] n is 1 or 2;

[0148] R 8 is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted by one or more R 9 ; wherein each R 9 is independently selected from hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (2-3C) alkenyl or (2-3C) alkynyl;

[0149] R 10 is -NR 11 R 12 wherein R 11 and R 12connected such that together with the nitrogen atom to which they are attached they form a 5-7 membered monocyclic heterocycle which is fused to a 5-6 membered monocyclic heteroaromatic ring or a benzene ring to form an 8-11 membered bicyclic heteroaromatic ring;

[0150] wherein R 10 any one or more rings present in are independently optionally substituted by one or more R 13 substituents;

[0151] each R 13 is independently selected from the group consisting of halogen, cyano, oxo, epoxy and the group

[0152] -L 1 -X 1 -Q 1 ;

[0153] wherein:

[0154] L 1 is absent or is (1-3C)alkylene;

[0155] 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 -, -SO2N(R 14 )- or -N(R 14 )SO2-, where R 14 is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl each time it appears, where any (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl in R 14 is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy;

[0156] Q 1 is selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, aryl, heterocyclic and heteroaryl, where any (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, aryl, heterocyclic or heteroaryl in Q 1 is optionally substituted by one or more groups R 15 ; and

[0157] each R 15independently selected from hydroxy, cyano, oxo, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR 15a R 15b 、-C(O)-R 15a 、-C(O)-OR 15a 、-OC(O)-R 15a 、-C(O)-NR 15a R 15b 、-N(R 15b )C(O)-R 15a 、-S(O) 0-2 R 15a 、-S(O)2NR 15a R 15b and -N(R 15b )-S(O)2R 15a The group consisting of R 15a and R 15b are each independently hydrogen or (1-3C)alkyl, and wherein R 15a or R 15b Any (1-3C)alkyl moiety present in the group is optionally replaced by one or more independently selected from hydroxy, cyano, halogen, -OR 15c 、-NR 15c R 15d and -C(O)-R 15c The substituents are further substituted, wherein R 15c and R 15d are all independently selected from hydrogen and (1-2C)alkyl.

[0158] Specific compounds of the present invention include, for example, compounds of formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, R 1 , R 2 , R 3 , R 4 , R 6 and R 10 (including R 11 and R 12 ) and any associated substituents each have any meaning as defined above or below in paragraphs (1) to (135):

[0159] (1)R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, halogen and (1-2C)alkoxy, provided that R 1 and R 3 at least one of which is a hydroxyl group;

[0160] (2)R 1 and R 3Independently selected from the group consisting of hydrogen, hydroxy, fluoro and (1-2C) alkoxy, provided that R 1 and R 3 at least one of which is hydroxy;

[0161] (3)R 1 and R 3 Independently selected from the group consisting of hydrogen, hydroxy, fluoro and methoxy, provided that R 1 and R 3 at least one of which is hydroxy.

[0162] (4)R 1 and R 3 are both hydroxy.

[0163] (5)R 2 is fluoro.

[0164] (6)R 2 is hydrogen.

[0165] (7)R 4 is selected from the group consisting of hydrogen, halogen, (1-4C) alkyl, (3-6C) cycloalkyl and (3-6C) cycloalkyl(1-2C) alkyl, wherein said (1-4C) alkyl is optionally substituted by one or more R 5a and said (3-6C) cycloalkyl and (3-6C) cycloalkyl(1-2C) alkyl are optionally substituted by one or more R 5b .

[0166] (8)R 4 is selected from the group consisting of hydrogen, halogen, (1-4C) alkyl, (3-5C) cycloalkyl and (3-5C) cycloalkyl(1-2C) alkyl, wherein said (1-4C) alkyl is optionally substituted by one, two or three R 5a and said (3-5C) cycloalkyl and (3-5C) cycloalkyl(1-2C) alkyl are optionally substituted by one, two or three R 5b .

[0167] (9)R 4 is selected from the group consisting of hydrogen, halogen, (1-4C) alkyl, (3-5C) cycloalkyl and (3-5C) cycloalkyl(1C) alkyl, wherein said (1-4C) alkyl is optionally substituted by one, two or three R 5a and said (3-5C) cycloalkyl and (3-5C) cycloalkyl(1C) alkyl are optionally substituted by one, two or three R 5b .

[0168] (10)R 4Selected from the group consisting of hydrogen, halogen, (1-4C) alkyl, and (3-5C) cycloalkyl, wherein said (1-4C) alkyl is optionally substituted with one or two R 5a substituents, and said (3-5C) cycloalkyl is optionally substituted with one or two R 5b substituents.

[0169] (11)R 4 Selected from the group consisting of hydrogen, fluorine, chlorine, (1-4C) alkyl, cyclopropyl, and cyclobutyl, wherein said (1-4C) alkyl is optionally substituted with one R 5a substituent, and said cyclopropyl and cyclobutyl are optionally substituted with one R 5b substituent.

[0170] (12)R 4 Selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl.

[0171] (13)R 4 Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl.

[0172] (14)R4 is selected from the group consisting of hydrogen, methyl, and ethyl.

[0173] (15)R4 is selected from the group consisting of hydrogen and methyl.

[0174] (16)R 4 is hydrogen.

[0175] (17)R 4 is methyl.

[0176] (18)Each R 5a is independently selected from halogen, hydroxy, or (1-3C) alkoxy.

[0177] (19)Each R 5a is independently selected from fluorine, chlorine, hydroxy, or (1-2C) alkoxy.

[0178] (20)Each R 5a is independently selected from fluorine, hydroxy, or methoxy.

[0179] (21)Each R 13 is independently selected from the group consisting of halogen, hydroxy, (1-3C) alkyl, and (1-3C) alkoxy.

[0180] (22)Each R 13 is independently selected from the group consisting of halogen, hydroxy, (1-2C) alkyl, and (1-2C) alkoxy.

[0181] (23)Each R 13Independently selected from the group consisting of fluorine, chlorine, hydroxyl, (1-2C) alkyl, and (1-2C) alkoxy.

[0182] (24) Each R 13 Independently selected from the group consisting of fluorine, chlorine, hydroxyl, methyl, and methoxy.

[0183] (25) R 7 Is hydrogen or (1-2C) alkyl.

[0184] (26) R 7 Is (1-3C) alkyl.

[0185] (27) R 7 Is hydrogen or methyl.

[0186] (28) R 7 Is hydrogen.

[0187] (29) R 7 Is methyl.

[0188] (30) n is 1.

[0189] (31) n is 2.

[0190] (32) R 8 Is phenyl or a 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R 9 Substituents.

[0191] (33) R 8 Is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from N and O, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 R 9 Substituents.

[0192] (34) R 8 Is phenyl or a 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 R 9 Substituents.

[0193] (35) R 8 Has any one of the following structures:

[0194]

[0195] Wherein R 9 As defined herein (or as defined in any one of paragraphs (44) to (50) below), each m 1 Independently is 0, 1, 2, or 3; and each m 2 Independently is 0, 1, or 2.

[0196] (36)R 8 has the following structure:

[0197]

[0198] where m 1 is 0, 1, 2 or 3, and R 9 is as defined herein (or as defined in any one of paragraphs (44) to (50) below).

[0199] (37)R 8 has any one of the following structures:

[0200]

[0201] where R 9 is as defined herein (or as defined in any one of paragraphs (44) to (50) below).

[0202] (38)R 8 has any one of the following structures:

[0203]

[0204] (39)R 8 has the following structure:

[0205]

[0206] (40)Each m 1 is independently 0, 1 or 2;

[0207] (41)Each m 1 is independently 0 or 1;

[0208] (42)Each m 1 is 0.

[0209] (43)Each m 2 is independently 0 or 1;

[0210] (44)Each R 9 is independently selected from the group consisting of cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl or (2-3C)alkynyl.

[0211] (45)Each R 9 is independently selected from the group consisting of halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl or (2-3C)alkynyl.

[0212] (46)Each R 9Independently selected from the group consisting of halogen, (1-3C) alkyl, (1-3C) alkoxy, (2C) alkenyl or (2C) alkynyl.

[0213] (47) Each R 9 Independently selected from the group consisting of halogen, (1-2C) alkyl, (1-2C) alkoxy, (2C) alkenyl and (2C) alkynyl.

[0214] (48) Each R 9 Independently selected from the group consisting of fluorine, chlorine, (1-3C) alkyl and (1-3C) alkoxy.

[0215] (49) Each R 9 Independently selected from the group consisting of fluorine, (1-2C) alkyl and (1-2C) alkoxy.

[0216] (50) Each R 9 Independently selected from the group consisting of fluorine, methyl and methoxy.

[0217] (51) R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form a 5-7 membered monocyclic heterocycle which is fused to a 5-6 membered monocyclic heteroaromatic ring or a benzene ring to form an 8-11 membered bicyclic heteroaromatic ring; wherein any ring is optionally substituted by one or more R 13 substituents.

[0218] (52) R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form a 5-6 membered monocyclic heterocycle which is fused to a 5-6 membered monocyclic heteroaromatic ring or a benzene ring to form an 8-10 membered bicyclic heteroaromatic ring; wherein any ring is optionally substituted by at most two R 13 substituents.

[0219] (53) R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following ring systems:

[0220]

[0221] wherein

[0222] v 2 and v 3 are each independently 1 or 2;

[0223] W 1 is CH, N or O;

[0224] each ring A is a benzene ring or a 5-6 membered heteroaromatic ring; and

[0225] Any ring is optionally substituted by one or two Rs 13 Substituted

[0226] (54)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following ring systems:

[0227]

[0228] wherein

[0229] v 2 and v 3 are each independently 1 or 2;

[0230] W 1 is CH, N or O;

[0231] Each ring A is a benzene ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N and O;

[0232] Each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen;

[0233] Each q 2 is independently 0, 1 or 2; and

[0234] Each q 3 is independently 0 or 1.

[0235] (55)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following ring systems:

[0236]

[0237] wherein

[0238] v 1 is 1, 2 or 3;

[0239] v 2 and v 3 are each independently 1 or 2;

[0240] W 1 is CH, N or O;

[0241] Each ring A is a benzene ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 N atoms;

[0242] Each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl, and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halogen;

[0243] Each q 2 is independently 0, 1, or 2; and

[0244] Each q 3 is independently 0 or 1.

[0245] (56)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0246]

[0247] wherein

[0248] Each q 2 is independently 0 or 1;

[0249] Each q 3 is independently 0, 1, or 2;

[0250] v 2 and v 3 are each independently 1 or 2;

[0251] W 2 、W 3 and W 4 are each independently CH, N, or O, provided that only zero, one, or two of W 2 、W 3 and W 4 are N or O;

[0252] W 5 、W 6 、W 7 and W 8 are each independently CH, N, or O, provided that only zero, one, or two of W 5 、W 6 、W 7 and W 8 are N or O;

[0253] W 9 is N, O, or CH2

[0254] W 10 is C or N;

[0255] W 11 , W 12 and W 13 are each independently CH, N or O, provided that W 11 , W 12 and W 13 Only zero, one, or two of them are N or O;

[0256] W 14 , W 15 , W 16 and W 17 are each independently CH, N or O, provided that W 14 , W 15 , W 16 and W 17 Only zero, one, or two of them are N or O;

[0257] W 18 Is N, O or CH2

[0258] W 19 is C or N; and

[0259] W 20 , W 21 , W 22 and W 23 are each independently CH, N or O, provided that W 20 , W 21 , W 22 and W 23 Only zero, one, or two of them are N or O.

[0260] (57)R 11 and R 12 are connected so that they form, together with the nitrogen atoms to which they are attached, any one of the following ring systems:

[0261]

[0262] in

[0263] Each q 2 is independently 0 or 1;

[0264] Each q 3 independently 0, 1 or 2;

[0265] v 2 and v 3 Each independently is 1 or 2;

[0266] W 2 , W 3 and W 4 are each independently CH or N, provided that W 2 , W3 and W 4 only zero, one or two of them are N;

[0267] W 5 , W 6 , W 7 and W 8 are each independently CH or N, provided that W 5 , W 6 , W 7 and W 8 only zero, one or two of them are N;

[0268] W 9 is N, O or CH2

[0269] W 10 is C or N;

[0270] W 11 , W 12 and W 13 are each independently CH or N, provided that W 11 , W 12 and W 13 only zero, one or two of them are N;

[0271] W 14 , W 15 , W 16 and W 17 are each independently CH or N, provided that W 14 , W 15 , W 16 and W 17 only zero, one or two of them are N;

[0272] W 18 is N, O or CH2

[0273] W 19 is C or N;

[0274] W 20 , W 21 , W 22 and W 23 are each independently CH or N, provided that W 20 , W 21 , W 22 and W 23 only zero, one or two of them are N; and

[0275] each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl and (1-3C)alkoxy, wherein R 13aAny (1-3C) alkyl and (1-3C) alkoxy in it is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen.

[0276] (58)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0277]

[0278] wherein any of the above rings is optionally substituted by 1, 2 or 3 R 13 substituents.

[0279] (59)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0280]

[0281]

[0282] wherein each q 2 is independently 0 or 1, and each q 3 is independently 0, 1 or 2.

[0283] (60)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0284]

[0285]

[0286] wherein

[0287] each q 2 is independently 0 or 1, and each q 3 is independently 0, 1 or 2; and

[0288] each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C) alkyl and (1-3C) alkoxy, wherein any (1-3C) alkyl and (1-3C) alkoxy in R 13a is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen.

[0289] (61)R 11 and R 12are linked such that together with the nitrogen atom to which they are linked they form the following ring systems:

[0290]

[0291] wherein

[0292] v 2 is 1 or 2;

[0293] ring A is a benzene ring or a 5-6 membered heteroaromatic ring; and

[0294] any ring is optionally substituted by one or two R 13 substituents.

[0295] (62)R 11 and R 12 are linked such that together with the nitrogen atom to which they are linked they form the following ring systems:

[0296]

[0297] wherein

[0298] v 2 is 1 or 2;

[0299] ring A is a benzene ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N and O;

[0300] each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen;

[0301] each q 2 is independently 0, 1 or 2; and

[0302] each q 3 is independently 0 or 1.

[0303] (63)R 11 and R 12 are linked such that together with the nitrogen atom to which they are linked they form the following ring systems:

[0304]

[0305] wherein

[0306] each q 2 is independently 0 or 1;

[0307] each q 3 is independently 0, 1 or 2;

[0308] v 3 is independently 1 or 2;

[0309] W 5 、W 6 、W 7 and W 8 are each independently CH or N, provided that W 5 、W 6 、W 7 and W 8 there are only zero, one or two N's among them; and

[0310] each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen.

[0311] (64)R 11 and R 12 are linked such that they together with the nitrogen atom to which they are attached form any one of the following cyclic systems:

[0312]

[0313] wherein v 3 is independently 1 or 2; and

[0314] any ring is optionally substituted by one or two R 13 substituents.

[0315] (65)R 11 and R 12 are linked such that they together with the nitrogen atom to which they are attached form any one of the following cyclic systems:

[0316]

[0317] wherein

[0318] each q 3 is independently 0 or 1;

[0319] each q 3 is independently 0, 1 or 2; and

[0320] v 3 is independently 1 or 2.

[0321] (66)R 11 and R 12connected such that together with the nitrogen atom to which they are attached they form any of the following cyclic systems:

[0322]

[0323] wherein

[0324] each q 3 is independently 0 or 1;

[0325] each q 3 is independently 0, 1 or 2;

[0326] v 3 is independently 1 or 2; and

[0327] each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen.

[0328] (67)R 11 and R 12 are connected such that together with the nitrogen atom to which they are attached they form the following cyclic system:

[0329]

[0330] wherein

[0331] each q 3 is independently 0 or 1;

[0332] each q 3 is independently 0, 1 or 2; and

[0333] v 3 is independently 1 or 2.

[0334] (68)R 11 and R 12 are connected such that together with the nitrogen atom to which they are attached they form the following cyclic system:

[0335]

[0336] wherein

[0337] each q 3 is independently 0 or 1;

[0338] each q 3 is independently 0, 1 or 2;

[0339] v 3is independently 1 or 2; and

[0340] Each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl, and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halogen.

[0341] (69)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0342]

[0343] wherein any of the above rings is optionally substituted with 1, 2, or 3 R 13 substituents.

[0344] (70)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0345]

[0346] wherein

[0347] each q 2 is independently 0 or 1, and each q 3 is independently 0, 1, or 2.

[0348] (71)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0349]

[0350] wherein

[0351] each q 2 is independently 0 or 1, and each q 3 is independently 0, 1, or 2; and

[0352] each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-3C)alkyl, and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R 13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halogen.

[0353] (72) Each R 13 is independently selected from the group consisting of halogen, oxo, epoxy, and the group -L 1 -X 1 -Q 1 (as defined in any one of paragraphs (80) to (101) or (126) to (135) above or below).

[0354] (73) Each R 13 is independently selected from the group consisting of halogen, epoxy, and the group -L 1 -X 1 -Q 1 (as defined in any one of paragraphs (97) to (101) or (133) to (135) above or below).

[0355] (74) Each R 13 is independently selected from the group consisting of fluorine, bromine, epoxy, and the group -L 1 -X 1 -Q 1 (as defined in any one of paragraphs (99) to (101) or (134) to (135) above or below).

[0356] (75) Each R 13 is independently selected from the group consisting of fluorine and the group -L 1 -X 1 -Q 1 (as defined in any one of paragraphs (100) or (101) or (134) to (135) above or below).

[0357] (76) Each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-2C)alkyl, and (1-2C)alkoxy, wherein any (1-2C)alkyl and (1-2C)alkoxy in R 13a are optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen.

[0358] (77) Each R 13a is independently selected from the group consisting of oxo, hydroxy, halogen, (1-2C)alkyl, and methyl, wherein any (1-2C)alkyl in R 13a is optionally substituted by one or more groups independently selected from the group consisting of hydroxy and halogen.

[0359] (78) Each R 13a is independently selected from the group consisting of oxo, hydroxy, (1-2C)alkyl, -CH2OH, -CH2F, -CHF2, -CF2, and methoxy.

[0360] (79) Each R 13aIndependently selected from the group consisting of oxo, hydroxy, (1-2C) alkyl, and -CH2OH.

[0361] (80)L 1 Absent or (1-2C) alkylene.

[0362] (81)L 1 Absent or methylene.

[0363] (82)L 1 Absent.

[0364] (83)L 1 Is methylene.

[0365] (84)X 1 Absent or 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 -, where R 14 is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, and (2-4C) alkenyl each time it appears, where any (1-4C) alkyl or (2-4C) alkenyl in R 14 is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy.

[0366] (85)X 1 Absent or selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl each time it appears, where any (1-4C) alkyl or (2-4C) alkenyl in R 14 is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy.

[0367] (86)X 1 Absent or selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl each time it appears, where any (1-4C) alkyl or (2-4C) alkenyl in R 14Any (1-4C) alkyl or (2-4C) alkenyl therein is independently optionally substituted by one, two or three groups selected from the group consisting of fluorine, chlorine and hydroxyl.

[0368] (87)X 1 Absent or selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl and (2-4C) alkenyl each time it appears.

[0369] (88)X 1 Absent or selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen, cyano and (1-2C) alkyl each time it appears.

[0370] (89)X 1 Absent or selected from the group consisting of -O-, -C(O)-O- and -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen and (1-2C) alkyl each time it appears.

[0371] (90)Q 1 Selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclic group and heteroaryl, wherein any (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclic group or heteroaryl in Q 1 is optionally substituted by one or more groups R 15 .

[0372] (91)Q 1 Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclic group and 5-6 membered heteroaryl, wherein any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl in Q 1 is optionally substituted by one or more groups R 15 .

[0373] (92)Q 1 Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclic group and 5-6 membered heteroaryl, wherein Q 1Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5- or 6-membered heterocyclic group or 5- or 6-membered heteroaryl in it is optionally substituted by one, two or three groups R 15 Substituted.

[0374] (93) Q 1 Is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N and O, and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N and O, where any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5- or 6-membered heterocyclic group or 5- or 6-membered heteroaryl in Q 1 Is optionally substituted by one, two or three groups R 15 Substituted.

[0375] (94) Q 1 Is selected from the group consisting of hydrogen, (1-4C) alkyl and 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N and O, where any (1-4C) alkyl or 5- or 6-membered heterocyclic group in Q 1 Is optionally substituted by one or more groups R 15 Substituted.

[0376] (95) Q 1 Is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl, where any (1-2C) alkyl or piperazinyl in Q 1 Is optionally substituted by one or more groups R 15 Substituted.

[0377] (96) Q 1 Is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl, where any (1-2C) alkyl or piperazinyl in Q 1 Is optionally substituted by one or more groups R 15 Substituted.

[0378] (97) L 1 Is absent or (1-2C) alkylene;

[0379] 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 -, where R 14 Is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl and (2-4C) alkenyl each time it appears, where R 14Any (1-4C) alkyl or (2-4C) alkenyl therein is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy; and

[0380] Q 1 is selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclic group and heteroaryl, wherein any (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclic group or heteroaryl in Q 1 is optionally substituted by one or more groups R 15 .

[0381] (98)L 1 is absent or (1-2C) alkylene;

[0382] X 1 is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl and (2-4C) alkenyl each time it appears, wherein any (1-4C) alkyl or (2-4C) alkenyl in R 14 is independently optionally substituted by one, two or three groups selected from the group consisting of fluorine, chlorine and hydroxy; and

[0383] Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclic group and 5-6 membered heteroaryl, wherein any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl in Q 1 is optionally substituted by one, two or three groups R 15 .

[0384] (99)L 1 is absent or (1-2C) alkylene;

[0385] X 1 is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl and (2-4C) alkenyl each time it appears; and

[0386] Q 1Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, a 5-6 membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N and O, and a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N and O, wherein Q 1 Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl group in 15 is optionally substituted by one, two or three groups R

[0387] (100)L 1 is absent or (1-2C) alkylene;

[0388] X 1 is absent or selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen, cyano and (1-2C) alkyl each time it appears; and

[0389] Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl, wherein any (1-2C) alkyl or piperazinyl in Q 1 is optionally substituted by one or more groups R 15 substituted.

[0390] (101)L 1 is absent or (1-2C) alkylene;

[0391] X 1 is absent or selected from the group consisting of -O-, -C(O)-O- and -NR 14 -, wherein R 14 is independently selected from the group consisting of hydrogen and (1-2C) alkyl each time it appears; and

[0392] Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl, wherein any (1-2C) alkyl or piperazinyl in Q 1 is optionally substituted by one or more groups R 15 substituted.

[0393] (102) Each R 15 is independently selected from the group consisting of hydroxy, cyano, oxo, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR 15a R 15b -, -C(O)-R 15a -, -C(O)-OR 15a -, -O-C(O)-R 15a, -C(O)-NR 15a R 15b and -N(R 15b )C(O)-R 15a group, where R 15a and R 15b are each independently hydrogen or (1-3C) alkyl, and where any (1-3C) alkyl moiety present in the R 15a or R 15b group is optionally further substituted by one or more substituents independently selected from hydroxy, cyano, halogen, -NR 15c R 15d , -C(O)-NR 15c R 15d and -N(R 15c )C(O)-R 15d group, where R 15c and R 15d are both independently selected from hydrogen and (1-2C) alkyl.

[0394] (103) Each R 15 is independently selected from the group consisting of hydroxy, cyano, oxo, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR 15a R 15b , -C(O)-NR 15a R 15b and -N(R 15b )C(O)-R 15a group, where R 15a and R 15b are each independently hydrogen or (1-3C) alkyl, and where any (1-3C) alkyl moiety present in the R 15a or R 15b group is optionally further substituted by one or more substituents independently selected from hydroxy, halogen and -NR 15c R 15d group, where R 15c and R 15d are both independently selected from hydrogen and (1-2C) alkyl.

[0395] (104) Each R 15 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR 15a R 15b and -C(O)-NR 15a R 15b group, where R 15a and R 15b are each independently hydrogen or (1-3C) alkyl.

[0396] (105) Each R15 Independently selected from the group consisting of a hydroxyl group, a cyano group, a halogen, a (1-3C) alkyl group, and -C(O)-NR 15a R 15b wherein R 15a and R 15b are each independently hydrogen or methyl.

[0397] (106) Each R 15 is independently selected from the group consisting of a hydroxyl group, a halogen, a (1-3C) alkyl group, and -C(O)-NR 15a R 15b wherein R 15a and R 15b are each independently hydrogen or methyl.

[0398] (107) Each R 15 is independently selected from the group consisting of a hydroxyl group, a (1-3C) alkyl group, and -C(O)-NR 15a R 15b wherein R 15a and R 15b are each independently hydrogen or methyl.

[0399] (108) Each R 15 is independently selected from the group consisting of a hydroxyl group, a halogen, and a (1-3C) alkyl group.

[0400] (109) R 6 is a (3-8C) cycloalkyl group, a (3-8C) cycloalkyl(1-2C) alkyl group, or a 4-7 membered heterocyclic ring group containing a heteroatom selected from N, O, or S, or a group having a structure according to formula (A) shown below:

[0401]

[0402] wherein n, R 7 and R 8 are each as defined herein.

[0403] (110) R 6 is a (3-6C) cycloalkyl group, a (3-6C) cycloalkyl(1-2C) alkyl group, or a 4-7 membered heterocyclic ring group containing a heteroatom selected from N, O, or S, or a group having a structure according to formula (A) shown below:

[0404]

[0405] wherein n, R 7 and R 8 are each as defined herein.

[0406] (111) R 6is a (3-6C) cycloalkyl group, a (3-6C) cycloalkyl(1-2C)alkyl group or a 5- or 6-membered heterocyclic group containing a heteroatom selected from O or S, or a group having a structure according to formula (A) shown below:

[0407]

[0408] wherein n, R 7 and R 8 are each as defined herein.

[0409] (112)R 6 is a (3-6C) cycloalkyl group, a (3-6C) cycloalkyl(1-2C)alkyl group or tetrahydropyran, or a group having a structure according to formula (A) shown below:

[0410]

[0411] wherein n, R 7 and R 8 are each as defined herein.

[0412] (113)R 6 is a (3-6C) cycloalkyl group or a (3-6C) cycloalkyl(1-2C)alkyl group, or a group having a structure according to formula (A) shown below:

[0413]

[0414] wherein n, R 7 and R 8 are each as defined herein.

[0415] (114)R 6 is a group having a structure according to formula (A) shown below:

[0416]

[0417] wherein n, R 7 and R 8 are each as defined herein.

[0418] (115)R 6 is a (1-6C)alkyl group, a (3-8C) cycloalkyl group, a (3-8C) cycloalkyl(1-2C)alkyl group or a 4-7 membered heterocyclic group containing a heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below:

[0419]

[0420]

[0421] wherein n, R7 and R 8 are each as defined herein.

[0422] (116)R 6 is (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or a 4-7 membered heterocyclic ring containing a heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below:

[0423]

[0424] wherein n, R 7 and R 8 are each as defined herein.

[0425] (117)R 6 is (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or a 5 or 6 membered heterocyclic ring containing a heteroatom selected from O or S, or a group having a structure according to formula (A) shown below:

[0426]

[0427] wherein n, R 7 and R 8 are each as defined herein.

[0428] (118)R 6 is (1-3C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or tetrahydropyran, or a group having a structure according to formula (A) shown below:

[0429]

[0430]

[0431] wherein n, R 7 and R 8 are each as defined herein.

[0432] (119)R 6 is (1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, or a group having a structure according to formula (A) shown below:

[0433]

[0434] wherein n, R 7 and R 8 are each as defined herein.

[0435] (120)R 6 is methyl

[0436] (121)R 6 is ethyl

[0437] (122)R 11 and R 12 are linked such that together with the nitrogen atom to which they are attached they form any one of the following cyclic systems:

[0438]

[0439]

[0440] wherein any of the above rings is optionally substituted by 1, 2 or 3 R 13 substituents.

[0441] (123) Each R 13 is independently selected from the group consisting of halogen, cyano, oxo, epoxy and the group -L 1 -X 1 -Q 1 (as defined anywhere herein).

[0442] (124) Each R 13 is independently selected from the group consisting of halogen, cyano, epoxy and the group -L 1 -X 1 -Q 1 (as defined anywhere herein or in any one of paragraphs (97) to (101) or (133) to (135)).

[0443] (125) Each R 13 is independently selected from the group consisting of fluorine, bromine, cyano, epoxy and the group -L 1 -X 1 -Q 1 (as defined anywhere herein or in any one of paragraphs (99) to (101) or (133) to (135)).

[0444] (126) 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 -, where R 14 is independently selected, at each occurrence, from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl and (2-4C)alkenyl, where R 14Any (1-4C) alkyl or (2-4C) alkenyl therein is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy.

[0445] (127)X 1 Absent or selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -C(O)-N(R 14 ), -N(R 14 )-C(O)- or -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen, cyano and (1-2C) alkyl each time it appears.

[0446] (128)X 1 Absent or selected from the group consisting of -O-, -C(O)-, -C(O)-N(R 14 ), -N(R 14 )-C(O)-, -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen and (1-2C) alkyl each time it appears.

[0447] (129)Q 1 Selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, aryl, aryl(1-3C)alkyl, heterocyclic group, heterocyclic group(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl, where any (1-6C) alkyl, (2-6C) alkenyl, aryl, aryl(1-3C)alkyl, heterocyclic group, heterocyclic group(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)alkyl in Q 1 is optionally substituted by one or more groups R 15 .

[0448] (130)Q 1 Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, aryl, aryl(1-2C)alkyl, heterocyclic group, heterocyclic group(1-2C)alkyl, heteroaryl and heteroaryl(1-2C)alkyl, where any (1-4C) alkyl, (2-4C) alkenyl, aryl, aryl(1-2C)alkyl, heterocyclic group, heterocyclic group(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl in Q 1 is optionally substituted by one or more groups R 15 .

[0449] (131)Q 1Selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1-2C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1-2C)alkyl, 4-6 membered heteroaryl and 4-6 membered heteroaryl(1-2C)alkyl, wherein Q 1 any of the (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1-2C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1-2C)alkyl, 4-6 membered heteroaryl or 4-6 membered heteroaryl(1-2C)alkyl in 15 is optionally substituted by one or more groups R

[0450] (132)Q 1 Selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1C)alkyl, 4-6 membered heteroaryl and 4-6 membered heteroaryl(1C)alkyl, wherein Q 1 any of the (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1C)alkyl, 4-6 membered heteroaryl or 4-6 membered heteroaryl(1C)alkyl in 15 is optionally substituted by one or more groups R

[0451] (133)L 1 is absent or (1-2C)alkylene;

[0452] X 1 is absent or 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 -, wherein R 14 is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl and (2-4C)alkenyl each time it appears, wherein any of the (1-4C)alkyl or (2-4C)alkenyl in R 14 is independently optionally substituted by one or more groups selected from the group consisting of halogen and hydroxy; and

[0453] Q 1 Selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclic group, heterocyclic group(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl, wherein Q 1Any (1-6C) alkyl, (2-6C) alkenyl, aryl, aryl(1-3C)alkyl, heterocyclic group, heterocyclic group(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)alkyl is optionally substituted by one or more groups R 15 substituted.

[0454] (134)L 1 is absent or is (1-2C) alkylene;

[0455] X 1 is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen, cyano and (1-2C) alkyl each time it appears; and

[0456] Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, aryl, aryl(1-2C)alkyl, heterocyclic group, heterocyclic group(1-2C)alkyl, heteroaryl and heteroaryl(1-2C)alkyl, where any (1-4C) alkyl, (2-4C) alkenyl, aryl, aryl(1-2C)alkyl, heterocyclic group, heterocyclic group(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl in Q 1 is optionally substituted by one or more groups R 15 substituted.

[0457] (135)L 1 is absent or is (1-2C) alkylene;

[0458] X 1 is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-N(R 14 )- and -N(R 14 )-C(O)-, -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen and (1-2C) alkyl each time it appears; and

[0459] Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1C)alkyl, 4-6 membered heteroaryl and 4-6 membered heteroaryl(1C)alkyl, where Q 1Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1C)alkyl, 4-6 membered heteroaryl or 4-6 membered heteroaryl(1C)alkyl is optionally substituted by one or more groups R 15 Substituted.

[0460] Suitably, R 1 and R 3 is as defined in any one of paragraphs (3) to (4) as numbered. Most suitably, R 1 and R 3 is as defined in paragraph (4) as numbered.

[0461] Suitably, R 2 is as defined in paragraph (6) as numbered.

[0462] Suitably, R 4 is as defined in any one of paragraphs (10) to (17) as numbered. More suitably, R 4 is as defined in any one of paragraphs (13) to (17) as numbered. Most suitably, R 4 is as defined in any one of paragraphs (15) to (17) as numbered.

[0463] Suitably, R 5a is as defined in any one of paragraphs (19) to (20) as numbered. Most suitably, R 5a is as defined in paragraph (20) as numbered.

[0464] Suitably, R 5b is as defined in any one of paragraphs (23) to (24) as numbered. Most suitably, R 5b is as defined in paragraph (24) as numbered.

[0465] Suitably, R 7 is as defined in any one of paragraphs (27) to (29) as numbered. Most suitably, R 7 is as defined in paragraph (28) as numbered.

[0466] Suitably, n is as defined in paragraph (30) as numbered.

[0467] Suitably, R 8 is as defined in any one of paragraphs (34) to (39) as numbered. More suitably, R 8 is as defined in any one of paragraphs (36) to (39) as numbered. Most suitably, R 8 is as defined in paragraph (39) as numbered.

[0468] Suitably, m 1As defined in numbered paragraph (41) or (42). Most suitably, m 1 As defined in numbered paragraph (42).

[0469] Suitably, R 9 As defined in any one of numbered paragraphs (46) to (50). More suitably, R 9 As defined in any one of numbered paragraphs (48) to (50). Most suitably, R 9 As defined in numbered paragraph (50).

[0470] Suitably, R 11 and R 12 As defined in any one of numbered paragraphs (53) to (71). More suitably, R 11 and R 12 As defined in any one of numbered paragraphs (57) to (71). Even more suitably, R 11 and R 12 As defined in any one of numbered paragraphs (61) to (71). Additionally even more suitably, R 11 and R 12 As defined in any one of numbered paragraphs (64) to (71). Still more suitably, R 11 and R 12 As defined in any one of numbered paragraphs (67) to (71). Most suitably, R 11 and R 12 As defined in any one of numbered paragraphs (70) to (71).

[0471] Suitably, R 11 and R 12 As defined in numbered paragraph (122).

[0472] Suitably, R 13 As defined in numbered paragraph (74) or (75).

[0473] Suitably, R 13a As defined in any one of numbered paragraphs (78) to (79).

[0474] Suitably, L 1 As defined in any one of numbered paragraphs (81) to (83).

[0475] Suitably, X 1 As defined in any one of numbered paragraphs (86) to (89). More suitably, X 1 As defined in any one of numbered paragraphs (88) to (89).

[0476] Suitably, X 1As defined in any one of numbered paragraphs (126) to (128). More preferably, X 1 As defined in numbered paragraph (128).

[0477] Preferably, Q 1 As defined in any one of numbered paragraphs (93) to (96). More preferably, Q 1 As defined in any one of numbered paragraphs (95) to (96).

[0478] Preferably, Q 1 As defined in any one of numbered paragraphs (129) to (132). More preferably, Q 1 As defined in any one of numbered paragraphs (130) to (132). Most preferably, Q 1 As defined in numbered paragraph (131) or (132).

[0479] Preferably, L 1 , X 1 and Q 1 As defined in any one of numbered paragraphs (99) to (101).

[0480] Preferably, L 1 , X 1 and Q 1 As defined in any one of numbered paragraphs (133) to (135). Most preferably, L 1 , X 1 and Q 1 As defined in numbered paragraph (134) or (135).

[0481] Preferably, R 15 As defined in any one of numbered paragraphs (105) to (108). More preferably, R 15 As defined in any one of numbered paragraphs (107) to (108).

[0482] Preferably, R 6 As defined in any one of numbered paragraphs (109) to (114). More preferably, R 6 As defined in any one of numbered paragraphs (111), (112), (113) or (114).

[0483] Preferably, R 6 As defined in any one of numbered paragraphs (115) to (121). More preferably, R 6 As defined in any one of numbered paragraphs (118), (119), (120) or (121).

[0484] In a specific group of compounds of the present invention, the compounds have a structure according to Formula II (which is a sub-definition of Formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0485]

[0486] Where n, R 2 , R 4 , R 7 , R 8 , R 10 and any related subunits are as defined in any numbered paragraph appearing above.

[0487] In embodiments of the compound of Formula II or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0488] R 2 as defined in numbered paragraph (5) or (6);

[0489] R 4 As defined in any of numbered paragraphs (10) to (17);

[0490] R 7 As defined in any of numbered paragraphs (27) to (29);

[0491] n as defined in numbered paragraph (30);

[0492] R 8 As defined in any of numbered paragraphs (31) to (39);

[0493] R 11 and R 12 As defined in any of numbered paragraphs (53) to (71); and

[0494] All other groups are as defined above in any numbered paragraph appearing therein.

[0495] In embodiments of the compound of Formula II or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0496] R 2 as defined in numbered paragraph (5) or (6);

[0497] R 4 As defined in any of numbered paragraphs (13) to (17);

[0498] R 7 As defined in any of numbered paragraphs (27) to (29);

[0499] n as defined in numbered paragraph (30);

[0500] R 8 as defined in any one of numbered paragraphs (34) to (39);

[0501] R 9 as defined in any one of numbered paragraphs (46) to (50);

[0502] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71);

[0503] R 13 as defined in numbered paragraph (74) or (75);

[0504] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0505] X 1 as defined in any one of numbered paragraphs (86) to (89);

[0506] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[0507] All other groups are as defined in any numbered paragraph as appears above.

[0508] In embodiments of the compounds of formula I-I or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0509] R 2 as defined in numbered paragraph (5) or (6);

[0510] R 4 as defined in any one of numbered paragraphs (13) to (17);

[0511] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0512] n is as defined in numbered paragraph (30);

[0513] R 8 as defined in any one of numbered paragraphs (36) to (39);

[0514] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0515] R 11 and R 12 as defined in any one of numbered paragraphs (57) to (71);

[0516] R 13 as defined in numbered paragraph (74) or (75);

[0517] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0518] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0519] X 1 as defined in any one of numbered paragraphs (86) to (89);

[0520] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[0521] All other groups are as defined in any numbered paragraph as appears above.

[0522] In embodiments of the compound of formula I-I or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0523] R 2 as defined in numbered paragraph (5) or (6);

[0524] R 4 as defined in any one of numbered paragraphs (13) to (17);

[0525] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0526] n is as defined in numbered paragraph (30);

[0527] R 8 as defined in any one of numbered paragraphs (36) to (39);

[0528] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0529] R 11 and R 12 as defined in any one of numbered paragraphs (61) to (71);

[0530] R 13 as defined in numbered paragraph (74) or (75);

[0531] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0532] L 1 as defined in any one of numbered paragraphs (81) to (93);

[0533] X 1 as defined in any one of numbered paragraphs (86) to (89);

[0534] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[0535] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0536] all other groups as defined in any numbered paragraph as appears above.

[0537] In an embodiment of the compound of formula I-I or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0538] R 2 as defined in numbered paragraph (5) or (6);

[0539] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0540] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0541] n is as defined in numbered paragraph (30);

[0542] R 8 as defined in any one of numbered paragraphs (36) to (39);

[0543] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0544] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71);

[0545] R 13 as defined in numbered paragraph (74) or (75);

[0546] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0547] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0548] X 1as defined in any one of numbered paragraphs (88) to (89);

[0549] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[0550] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0551] all other groups are as defined in any numbered paragraph as above appears.

[0552] In embodiments of the compound of formula I-I or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0553] R 2 as defined in numbered paragraph (6);

[0554] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0555] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0556] n is as defined in numbered paragraph (30);

[0557] R 8 as defined in any one of numbered paragraphs (36) to (39);

[0558] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0559] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71);

[0560] R 13 as defined in numbered paragraph (74) or (75);

[0561] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0562] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0563] X 1 as defined in any one of numbered paragraphs (88) to (89);

[0564] Q 1as defined in any one of numbered paragraphs (95) to (96);

[0565] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0566] all other groups are as defined in any numbered paragraph as set forth above.

[0567] In embodiments of the compounds of Formula I-I or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0568] R 2 as defined in numbered paragraph (6);

[0569] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0570] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0571] n is as defined in numbered paragraph (30);

[0572] R 8 as defined in any one of numbered paragraphs (36) to (39);

[0573] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0574] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71);

[0575] R 13 as defined in numbered paragraph (74) or (75);

[0576] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0577] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[0578] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0579] all other groups are as defined in any numbered paragraph as set forth above.

[0580] In embodiments of the compound of formula I-I or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0581] R 2 is as defined in numbered paragraph (6);

[0582] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[0583] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0584] n is as defined in numbered paragraph (30);

[0585] R 8 is as defined in numbered paragraph (39);

[0586] R 11 and R 12 are as defined in any one of numbered paragraphs (67) to (71);

[0587] R 13 is as defined in numbered paragraph (74) or (75);

[0588] R 13a is as defined in any one of numbered paragraphs (78) to (79);

[0589] L 1 、X 1 and Q 1 are as defined in any one of numbered paragraphs (99) to (101);

[0590] R 15 is as defined in any one of numbered paragraphs (107) to (108); and

[0591] All other groups are as defined in any numbered paragraph as they appear above.

[0592] In embodiments of the compound of formula I-I or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0593] R 2 is as defined in numbered paragraph (6);

[0594] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[0595] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0596] n as defined in numbered paragraph (30);

[0597] R 8 As defined in numbered paragraph (39);

[0598] R 11 and R 12 As defined in any of numbered paragraphs (70) to (71);

[0599] R 13 As defined in numbered paragraph (74) or (75);

[0600] R 13a As defined in any of numbered paragraphs (78) to (79);

[0601] L 1 , X 1 and Q 1 As defined in any of numbered paragraphs (99) to (101);

[0602] R 15 As defined in any of numbered paragraphs (107) to (108); and

[0603] All other groups are as defined above in any numbered paragraph appearing therein.

[0604] In embodiments of the compound of Formula II or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0605] R 2 As defined in numbered paragraph (6);

[0606] R 4 As defined in numbered paragraph (15);

[0607] R 7 As defined in numbered paragraph (27);

[0608] n as defined in numbered paragraph (30);

[0609] R 8 As defined in numbered paragraph (39);

[0610] R 11 and R 12 as defined in numbered paragraph (70);

[0611] R 13 As defined in numbered paragraph (74);

[0612] R 13a as defined in numbered paragraph (78);

[0613] L 1 、X 1 and Q 1 as defined in numbered paragraph (99);

[0614] R 15 as defined in numbered paragraph (107); and

[0615] all other groups as defined in any numbered paragraph as above appears.

[0616] In embodiments of the compounds of formula I-I or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0617] R 2 as defined in numbered paragraph (6);

[0618] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0619] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0620] n is as defined in numbered paragraph (30);

[0621] R 8 as defined in numbered paragraph (39);

[0622] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71) or (122);

[0623] R 13 as defined in numbered paragraphs (74), (75) or (123) to (125);

[0624] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0625] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[0626] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0627] all other groups as defined in any numbered paragraph as above appears.

[0628] In embodiments of the compounds of formula I-I or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[0629] R 2 as defined in numbered paragraph (6);

[0630] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0631] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0632] n is as defined in numbered paragraph (30);

[0633] R 8 as defined in numbered paragraph (39);

[0634] R 11 and R 12 as defined in any one of numbered paragraphs (70) to (71) or (122);[[ID=—31]]

[0635] R 13 as defined in numbered paragraphs (74), (75), or (124) to (125);

[0636] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0637] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (134) to (135);

[0638] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0639] All other groups are as defined in any numbered paragraph as they appear above.

[0640] In embodiments of the compounds of formula I-I or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[0641] R 2 as defined in numbered paragraph (6);

[0642] R 4 as defined in numbered paragraph (15);

[0643] R 7 as defined in numbered paragraph (27);

[0644] as defined in numbered paragraph (30);

[0645] R 8 as defined in numbered paragraph (39);

[0646] R 11 and R 12 as defined in numbered paragraph (122);

[0647] R 13 as defined in numbered paragraph (74) or (124);

[0648] R 13a as defined in numbered paragraph (78);

[0649] L 1 、X 1 and Q 1 as defined in numbered paragraph (134) or (135);

[0650] R 15 as defined in numbered paragraph (107); and

[0651] all other groups are defined in any numbered paragraph as they appear above. In a particular group of compounds of the invention, the compounds have a structure according to formula I-I (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0652]

[0653] wherein n, m 1 、R 1 、R 2 、R 3 、R 4 、R 7 、R 9 、R 10 and any related subunits are defined in any numbered paragraph as they appear above.

[0654] In embodiments of the compounds of formula I-II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0655] m 1 as defined in numbered paragraph (41) or (42);

[0656] R 2 as defined in numbered paragraph (5) or (6);

[0657] R 4 as defined in any one of numbered paragraphs (10) to (17);

[0658] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0659] n as defined in numbered paragraph (30);

[0660] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71); and

[0661] all other groups as defined in any numbered paragraph as they appear above.

[0662] In embodiments of the compounds of formulae I - II or their pharmaceutically acceptable salts, hydrates and / or solvates:

[0663] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[0664] m 1 as defined in numbered paragraph (41) or (42);

[0665] R 2 as defined in numbered paragraph (5) or (6);

[0666] R 4 as defined in any one of numbered paragraphs (13) to (17);

[0667] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0668] n as defined in numbered paragraph (30);

[0669] R 9 as defined in any one of numbered paragraphs (46) to (50);

[0670] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71);

[0671] R 13 as defined in numbered paragraph (74) or (75);

[0672] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0673] X 1 as defined in any one of numbered paragraphs (86) to (89);

[0674] Q1 as defined in any one of numbered paragraphs (93) to (96);

[0675] All other groups are as defined in any numbered paragraph as above.

[0676] In embodiments of the compounds of formulae I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0677] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[0678] m 1 is as defined in numbered paragraph (41) or (42);

[0679] R 2 is as defined in numbered paragraph (5) or (6);

[0680] R 4 is as defined in any one of numbered paragraphs (13) to (17);

[0681] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0682] n is as defined in numbered paragraph (30);

[0683] R 9 is as defined in any one of numbered paragraphs (48) to (50);

[0684] R 11 and R 12 are as defined in any one of numbered paragraphs (57) to (71);

[0685] R 13 is as defined in numbered paragraph (74) or (75);

[0686] R 13a is as defined in any one of numbered paragraphs (78) to (79);

[0687] L 1 is as defined in any one of numbered paragraphs (81) to (83);

[0688] X 1 is as defined in any one of numbered paragraphs (86) to (89);

[0689] Q 1 is as defined in any one of numbered paragraphs (93) to (96);

[0690] All other groups are defined as in any numbered paragraph as set forth above.

[0691] In embodiments of the compounds of Formulae I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0692] R 1 and R 3 are defined as in any one of numbered paragraphs (3) to (4);

[0693] m 1 is defined as in numbered paragraph (41) or (42);

[0694] R 2 is defined as in numbered paragraph (5) or (6);

[0695] R 4 is defined as in any one of numbered paragraphs (13) to (17);

[0696] R 7 is defined as in any one of numbered paragraphs (27) to (29);

[0697] n is defined as in numbered paragraph (30);

[0698] R 9 is defined as in any one of numbered paragraphs (48) to (50);

[0699] R 11 and R 12 are defined as in any one of numbered paragraphs (61) to (71);

[0700] R 13 is defined as in numbered paragraph (74) or (75);

[0701] R 13a is defined as in any one of numbered paragraphs (78) to (79);

[0702] L 1 is defined as in any one of numbered paragraphs (81) to (93);

[0703] X 1 is defined as in any one of numbered paragraphs (86) to (89);

[0704] Q 1 is defined as in any one of numbered paragraphs (93) to (96);

[0705] R 15 is defined as in any one of numbered paragraphs (105) to (108); and

[0706] All other groups are as defined in any numbered paragraph as presented above.

[0707] In embodiments of the compounds of Formulae I - II or their pharmaceutically acceptable salts, hydrates and / or solvates:

[0708] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[0709] m 1 is as defined in numbered paragraph (41) or (42);

[0710] R 2 is as defined in numbered paragraph (5) or (6);

[0711] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[0712] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0713] n is as defined in numbered paragraph (30);

[0714] R 9 is as defined in any one of numbered paragraphs (48) to (50);

[0715] R 11 and R 12 are as defined in any one of numbered paragraphs (64) to (71);

[0716] R 13 is as defined in numbered paragraph (74) or (75);

[0717] R 13a is as defined in any one of numbered paragraphs (78) to (79);

[0718] L 1 is as defined in any one of numbered paragraphs (81) to (83);

[0719] X 1 is as defined in any one of numbered paragraphs (88) to (89);

[0720] Q 1 is as defined in any one of numbered paragraphs (95) to (96);

[0721] R 15 is as defined in any one of numbered paragraphs (105) to (108); and

[0722] All other groups are as defined in any numbered paragraph as set forth above.

[0723] In embodiments of the compounds of Formulae I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0724] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[0725] m 1 is as defined in numbered paragraph (41) or (42);

[0726] R 2 is as defined in numbered paragraph (6);

[0727] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[0728] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0729] n is as defined in numbered paragraph (30);

[0730] R 9 is as defined in any one of numbered paragraphs (48) to (50);

[0731] R 11 and R 12 are as defined in any one of numbered paragraphs (64) to (71);

[0732] R 13 is as defined in numbered paragraph (74) or (75);

[0733] R 13a is as defined in any one of numbered paragraphs (78) to (79);

[0734] L 1 is as defined in any one of numbered paragraphs (81) to (83);

[0735] X 1 is as defined in any one of numbered paragraphs (88) to (89);

[0736] Q 1 is as defined in any one of numbered paragraphs (95) to (96);

[0737] R 15 is as defined in any one of numbered paragraphs (105) to (108); and

[0738] All other groups are as defined in any numbered paragraph as set forth above.

[0739] In embodiments of the compounds of Formulas I - II or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[0740] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[0741] m 1 is as defined in numbered paragraph (41) or (42);

[0742] R 2 is as defined in numbered paragraph (6);

[0743] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[0744] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0745] n is as defined in numbered paragraph (30);

[0746] R 9 is as defined in any one of numbered paragraphs (48) to (50);

[0747] R 11 and R 12 are as defined in any one of numbered paragraphs (67) to (71);

[0748] R 13 is as defined in numbered paragraph (74) or (75);

[0749] R 13a is as defined in any one of numbered paragraphs (78) to (79);

[0750] L 1 、X 1 and Q 1 are as defined in any one of numbered paragraphs (99) to (101);

[0751] R 15 is as defined in any one of numbered paragraphs (105) to (108); and

[0752] All other groups are as defined in any numbered paragraph as set forth above.

[0753] In embodiments of the compounds of Formulas I - II or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[0754] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[0755] m 1 as defined in numbered paragraph (41) or (42);

[0756] R 2 as defined in numbered paragraph (6);

[0757] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0758] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0759] n as defined in numbered paragraph (30);

[0760] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0761] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71);

[0762] R 13 as defined in numbered paragraph (74) or (75);

[0763] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0764] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[0765] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0766] all other groups as defined in any numbered paragraph as appears above.

[0767] In embodiments of the compounds of formula I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0768] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[0769] m 1as defined in numbered paragraph (41) or (42);

[0770] R 2 as defined in numbered paragraph (6);

[0771] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0772] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0773] n as defined in numbered paragraph (30);

[0774] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0775] R 11 and R 12 as defined in any one of numbered paragraphs (70) to (71);

[0776] R 13 as defined in numbered paragraph (74) or (75);

[0777] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0778] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[0779] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0780] all other groups as defined in any numbered paragraph as appears above.

[0781] In embodiments of the compounds of formulae I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0782] R 1 and R 3 as defined in numbered paragraph (3);

[0783] m 1 as defined in numbered paragraph (41);

[0784] R 2 as defined in numbered paragraph (6);

[0785] R 4as defined in numbered paragraph (15);

[0786] R 7 as defined in numbered paragraph (27);

[0787] n as defined in numbered paragraph (30);

[0788] R 9 as defined in numbered paragraph (48);

[0789] R 11 and R 12 as defined in numbered paragraph (70);

[0790] R 13 as defined in numbered paragraph (74);

[0791] R 13a as defined in numbered paragraph (78);

[0792] L 1 、X 1 and Q 1 as defined in numbered paragraph (99);

[0793] R 15 as defined in numbered paragraph (107); and

[0794] all other groups as defined in any numbered paragraph as appears above.

[0795] In embodiments of the compounds of Formulae I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0796] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[0797] m 1 as defined in numbered paragraph (41) or (42);

[0798] R 2 as defined in numbered paragraph (6);

[0799] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0800] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0801] n as defined in numbered paragraph (30);

[0802] R 9as defined in any one of numbered paragraphs (48) to (50);

[0803] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71) or (122);

[0804] R 13 as defined in any one of numbered paragraphs (74), (75) or (123) to (125);

[0805] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0806] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[0807] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0808] all other groups are as defined in any numbered paragraph as above where they appear.

[0809] In embodiments of the compounds of formulae I - II or their pharmaceutically acceptable salts, hydrates and / or solvates:

[0810] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[0811] m 1 is as defined in numbered paragraph (41) or (42);

[0812] R 2 is as defined in numbered paragraph (6);

[0813] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[0814] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[0815] n is as defined in numbered paragraph (30);

[0816] R 9 is as defined in any one of numbered paragraphs (48) to (50);

[0817] R 11 and R12 as defined in any one of numbered paragraphs (70) to (71) or (122);

[0818] R 13 as defined in any one of numbered paragraphs (74), (75) or (124) to (125);

[0819] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0820] L 1 , X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (134) to (135);

[0821] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0822] all other groups as defined in any numbered paragraph as appears above.

[0823] In embodiments of the compounds of Formula I - II or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0824] R 1 and R 3 as defined in numbered paragraph (3);

[0825] m 1 as defined in numbered paragraph (41);

[0826] R 2 as defined in numbered paragraph (6);

[0827] R 4 as defined in numbered paragraph (15);

[0828] R 7 as defined in numbered paragraph (27);

[0829] n is as defined in numbered paragraph (30);

[0830] R 9 as defined in numbered paragraph (48);

[0831] R 11 and R 12 as defined in numbered paragraph (122);

[0832] R 13 as defined in numbered paragraph (74) or (123);

[0833] R 13a as defined in numbered paragraph (78);

[0834] L 1 、X 1 and Q 1 as defined in numbered paragraph (134) or (135);

[0835] R 15 as defined in numbered paragraph (107); and

[0836] all other groups as defined in any numbered paragraph as appears above.

[0837] In a specific group of compounds of the invention, the compounds have a structure according to Formulae I-III (which are sub-definitions of Formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0838]

[0839] wherein n, m 1 、R 2 、R 4 、R 7 、R 9 、R 10 and any related subunits as defined in any numbered paragraph as appears above.

[0840] In embodiments of the compounds of Formulae I-III or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0841] m 1 as defined in numbered paragraph (41) or (42);

[0842] R 2 as defined in numbered paragraph (5) or (6);

[0843] R 4 as defined in any one of numbered paragraphs (10) to (17);

[0844] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0845] n as defined in numbered paragraph (30);

[0846] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71); and

[0847] all other groups as defined in any numbered paragraph as appears above.

[0848] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0849] m 1 As defined in numbered paragraph (41) or (42);

[0850] R 2 As defined in numbered paragraph (5) or (6);

[0851] R 4 As defined in any one of numbered paragraphs (13) to (17);

[0852] R 7 As defined in any one of numbered paragraphs (27) to (29);

[0853] n is as defined in numbered paragraph (30);

[0854] R 9 As defined in any one of numbered paragraphs (46) to (50);

[0855] R 11 and R 12 As defined in any one of numbered paragraphs (53) to (71);

[0856] R 13 As defined in numbered paragraph (74) or (75);

[0857] L 1 As defined in any one of numbered paragraphs (81) to (83);

[0858] X 1 As defined in any one of numbered paragraphs (86) to (89);

[0859] Q 1 As defined in any one of numbered paragraphs (93) to (96);

[0860] All other groups are as defined in any numbered paragraph as they appear above.

[0861] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0862] m 1 As defined in numbered paragraph (41) or (42);

[0863] R 2 As defined in numbered paragraph (5) or (6);

[0864] R 4as defined in any one of numbered paragraphs (13) to (17);

[0865] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0866] n as defined in numbered paragraph (30);

[0867] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0868] R 11 and R 12 as defined in any one of numbered paragraphs (57) to (71);

[0869] R 13 as defined in numbered paragraph (74) or (75);

[0870] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0871] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0872] X 1 as defined in any one of numbered paragraphs (86) to (89);

[0873] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[0874] All other groups are as defined in any numbered paragraph as appears above.

[0875] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0876] m 1 as defined in numbered paragraph (41) or (42);

[0877] R 2 as defined in numbered paragraph (5) or (6);

[0878] R 4 as defined in any one of numbered paragraphs (13) to (17);

[0879] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0880] n as defined in numbered paragraph (30);

[0881] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0882] R 11 and R 12 as defined in any one of numbered paragraphs (61) to (71);

[0883] R 13 as defined in numbered paragraph (74) or (75);

[0884] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0885] L 1 as defined in any one of numbered paragraphs (81) to (93);

[0886] X 1 as defined in any one of numbered paragraphs (86) to (89);

[0887] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[0888] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0889] all other groups as defined in any numbered paragraph as above appearing.

[0890] In embodiments of the compounds of formulae I - III or their pharmaceutically acceptable salts, hydrates and / or solvates:

[0891] m 1 as defined in numbered paragraph (41) or (42);

[0892] R 2 as defined in numbered paragraph (5) or (6);

[0893] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0894] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0895] n as defined in numbered paragraph (30);

[0896] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0897] R11 and R 12 as defined in any one of numbered paragraphs (64) to (71);

[0898] R 13 as defined in numbered paragraph (74) or (75);

[0899] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0900] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0901] X 1 as defined in any one of numbered paragraphs (88) to (89);

[0902] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[0903] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0904] all other groups as defined in any numbered paragraph as appears above.

[0905] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0906] m 1 as defined in numbered paragraph (41) or (42);

[0907] R 2 as defined in numbered paragraph (6);

[0908] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0909] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0910] n as defined in numbered paragraph (30);

[0911] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0912] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71);

[0913] R13 as defined in numbered paragraph (74) or (75);

[0914] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0915] L 1 as defined in any one of numbered paragraphs (81) to (83);

[0916] X 1 as defined in any one of numbered paragraphs (88) to (89);

[0917] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[0918] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0919] all other groups as defined in any numbered paragraph as appears above.

[0920] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0921] m 1 as defined in numbered paragraph (41) or (42);

[0922] R 2 as defined in numbered paragraph (6);

[0923] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0924] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0925] n as defined in numbered paragraph (30);

[0926] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0927] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71);

[0928] R 13 as defined in numbered paragraph (74) or (75);

[0929] R 13aas defined in any one of numbered paragraphs (78) to (79);

[0930] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[0931] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[0932] all other groups are as defined in any numbered paragraph as they appear above.

[0933] In embodiments of the compounds of formulae I - III or their pharmaceutically acceptable salts, hydrates and / or solvates:

[0934] m 1 as defined in numbered paragraph (41) or (42);

[0935] R 2 as defined in numbered paragraph (6);

[0936] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0937] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0938] n is as defined in numbered paragraph (30);

[0939] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0940] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71);

[0941] R 13 as defined in numbered paragraph (74) or (75);

[0942] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0943] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[0944] R 15as defined in any one of numbered paragraphs (107) to (108); and

[0945] All other groups are as defined in any numbered paragraph as above.

[0946] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0947] m 1 as defined in numbered paragraph (41) or (42);

[0948] R 2 as defined in numbered paragraph (6);

[0949] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0950] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0951] n is as defined in numbered paragraph (30);

[0952] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0953] R 11 and R 12 as defined in any one of numbered paragraphs (70) to (71);

[0954] R 13 as defined in numbered paragraph (74) or (75);

[0955] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0956] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[0957] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0958] All other groups are as defined in any numbered paragraph as above.

[0959] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0960] m 1as defined in numbered paragraph (41);

[0961] R 2 as defined in numbered paragraph (6);

[0962] R 4 as defined in numbered paragraph (15);

[0963] R 7 as defined in numbered paragraph (27);

[0964] n as defined in numbered paragraph (30);

[0965] R 9 as defined in numbered paragraph (48);

[0966] R 11 and R 12 as defined in numbered paragraph (70);

[0967] R 13 as defined in numbered paragraph (74);

[0968] R 13a as defined in numbered paragraph (78);

[0969] L 1 、X 1 and Q 1 as defined in numbered paragraph (99);

[0970] R 15 as defined in numbered paragraph (107); and

[0971] all other groups as defined in any numbered paragraph as they appear above.

[0972] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0973] m 1 as defined in numbered paragraph (41) or (42);

[0974] R 2 as defined in numbered paragraph (6);

[0975] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0976] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0977] n as defined in numbered paragraph (30);

[0978] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0979] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71) or (122);

[0980] R 13 as defined in numbered paragraphs (74), (75) or (123) to (125);

[0981] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0982] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[0983] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0984] all other groups as defined in any numbered paragraph as appears above.

[0985] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0986] m 1 as defined in numbered paragraphs (41) or (42);

[0987] R 2 as defined in numbered paragraph (6);

[0988] R 4 as defined in any one of numbered paragraphs (15) to (17);

[0989] R 7 as defined in any one of numbered paragraphs (27) to (29);

[0990] n is as defined in numbered paragraph (30);

[0991] R 9 as defined in any one of numbered paragraphs (48) to (50);

[0992] R 11 and R 12 as defined in any one of numbered paragraphs (70) to (71) or (122);

[0993] R 13 as defined in numbered paragraphs (74), (75) or (124) to (125);

[0994] R 13a as defined in any one of numbered paragraphs (78) to (79);

[0995] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (134) to (135);

[0996] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[0997] all other groups as defined in any numbered paragraph as appears above.

[0998] In embodiments of the compounds of formulae I - III or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[0999] m 1 as defined in numbered paragraph (41);

[1000] R 2 as defined in numbered paragraph (6);

[1001] R 4 as defined in numbered paragraph (15);

[1002] R 7 as defined in numbered paragraph (27);

[1003] n as defined in numbered paragraph (30);

[1004] R 9 as defined in numbered paragraph (48);

[1005] R 11 and R 12 as defined in numbered paragraph (122);

[1006] R 13 as defined in numbered paragraph (74) or (123);

[1007] R 13a as defined in numbered paragraph (78);

[1008] L 1 、X 1 and Q 1As defined in numbered paragraph (134) or (135);

[1009] R 15 As defined in numbered paragraph (107); and

[1010] All other groups are as defined in any numbered paragraph as above appears.

[1011] In a specific group of compounds of the invention, the compound has a structure according to formulae I-IV (which are sub-definitions of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1012]

[1013] Wherein

[1014] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in numbered paragraph (53) above; and

[1015] Wherein n, R 2 R 4 R 7 and R 8 and any related subunits are as defined in any numbered paragraph as above appears.

[1016] In a specific group of compounds of the invention, the compound has a structure according to formulae I-V (which are sub-definitions of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1017]

[1018] Wherein

[1019] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in paragraph (56) above; and

[1020] Wherein n, R 2 R 4 R 7 and R 8 and any related subunits are as defined in any numbered paragraph as above appears.

[1021] In a specific group of compounds of the invention, the compound has a structure according to formulae I-VI (which are sub-definitions of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1022]

[1023] wherein

[1024] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in numbered paragraphs (65) or (66) above; and wherein n, R 2 、R 4 、R 7 and R 8 and any related subunits are as defined in any numbered paragraph as set forth above.

[1025] In a specific group of compounds of the present invention, the compounds have a structure according to Formulas I - VII (which are sub - definitions of Formula I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[1026]

[1027] wherein

[1028] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in paragraph (68) above; and

[1029] wherein n, R 2 、R 4 、R 7 and R 8 and any related subunits are as defined in any numbered paragraph as set forth above.

[1030] In a specific group of compounds of the present invention, the compounds have a structure according to Formulas I - VIII (which are sub - definitions of Formula I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[1031]

[1032] wherein

[1033] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in numbered paragraphs (70) or (71) above; and wherein n, R 2 、R 4 、R 7and R 8 and any related subunits as defined in any numbered paragraph above where they appear.

[1034] In one group of specific compounds of the present invention, the compounds have a structure according to Formulae I - VIIIa (which are sub - definitions of Formula I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[1035]

[1036] wherein

[1037] R 10 is - NR 11 R 12 and R 11 and R 12 are as defined in paragraph (122) above; and

[1038] where n, R 2 R 4 R 7 and R 8 and any related subunits are as defined in any numbered paragraph above where they appear.

[1039] In embodiments of the compounds of Formulae I - IV, I - V, I - VI, I - VII, or I - VIII, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[1040] R 2 is as defined in numbered paragraph (5) or (6);

[1041] R 4 is as defined in any one of numbered paragraphs (10) to (17);

[1042] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[1043] n is as defined in numbered paragraph (30);

[1044] R 8 is as defined in any one of numbered paragraphs (31) to (39); and

[1045] all other groups are as defined in any numbered paragraph above where they appear.

[1046] In embodiments of the compounds of Formulae I - IV, I - V, I - VI, I - VII, or I - VIII, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[1047] R 2as defined in numbered paragraph (5) or (6);

[1048] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1049] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1050] n as defined in numbered paragraph (30);

[1051] R 8 as defined in any one of numbered paragraphs (34) to (39);

[1052] R 9 as defined in any one of numbered paragraphs (46) to (50);

[1053] R 13 as defined in numbered paragraph (74) or (75);

[1054] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1055] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1056] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1057] All other groups are as defined in any numbered paragraph as above.

[1058] In embodiments of the compounds of Formulas I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1059] R 2 as defined in numbered paragraph (5) or (6);

[1060] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1061] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1062] n as defined in numbered paragraph (30);

[1063] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1064] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1065] R 13 as defined in numbered paragraph (74) or (75);

[1066] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1067] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1068] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1069] All other groups are as defined in any numbered paragraph as appears above.

[1070] In embodiments of the compounds of formulae I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1071] R 2 as defined in numbered paragraph (5) or (6);

[1072] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1073] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1074] n is as defined in numbered paragraph (30);

[1075] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1076] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1077] R 13 as defined in numbered paragraph (74) or (75);

[1078] L 1 as defined in any one of numbered paragraphs (81) to (93);

[1079] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1080] Q1 as defined in any one of numbered paragraphs (93) to (96);

[1081] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1082] all other groups as defined in any numbered paragraph as appears above.

[1083] In embodiments of the compounds of Formulae I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1084] R 2 as defined in numbered paragraph (5) or (6);

[1085] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1086] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1087] n is as defined in numbered paragraph (30);

[1088] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1089] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1090] R 13 as defined in numbered paragraph (74) or (75);

[1091] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1092] X 1 as defined in any one of numbered paragraphs (88) to (89);

[1093] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[1094] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1095] all other groups as defined in any numbered paragraph as appears above.

[1096] In embodiments of a compound of Formula I-IV, I-V, I-VI, I-VII or I-VIII or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1097] R 2 As defined in numbered paragraph (6);

[1098] R 4 As defined in any one of numbered paragraphs (15) to (17);

[1099] R 7 As defined in any one of numbered paragraphs (27) to (29);

[1100] n is as defined in numbered paragraph (30);

[1101] R 8 As defined in any one of numbered paragraphs (36) to (39);

[1102] R 9 As defined in any one of numbered paragraphs (48) to (50);

[1103] R 13 As defined in numbered paragraph (74) or (75);

[1104] L 1 As defined in any one of numbered paragraphs (81) to (83);

[1105] X 1 As defined in any one of numbered paragraphs (88) to (89);

[1106] Q 1 As defined in any one of numbered paragraphs (95) to (96);

[1107] R 15 As defined in any one of numbered paragraphs (105) to (108); and

[1108] All other groups are as defined in any numbered paragraph as appears above.

[1109] In embodiments of a compound of Formula I-IV, I-V, I-VI, I-VII or I-VIII or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1110] R 2 As defined in numbered paragraph (6);

[1111] R 4 As defined in any one of numbered paragraphs (15) to (17);

[1112] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1113] n as defined in numbered paragraph (30);

[1114] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1115] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1116] R 13 as defined in numbered paragraph (74) or (75);

[1117] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1118] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1119] all other groups as defined in any numbered paragraph as they appear above.

[1120] In embodiments of the compounds of Formulae I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1121] R 2 as defined in numbered paragraph (6);

[1122] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1123] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1124] n as defined in numbered paragraph (30);

[1125] R 8 as defined in numbered paragraph (39);

[1126] R 13 as defined in numbered paragraph (74) or (75);

[1127] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1128] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1129] all other groups are as defined in any numbered paragraph as appearing above.

[1130] In embodiments of the compounds of formulae I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1131] R 2 as defined in numbered paragraph (6);

[1132] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1133] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1134] n is as defined in numbered paragraph (30);

[1135] R 8 as defined in numbered paragraph (39);

[1136] R 13 as defined in numbered paragraph (74) or (75);

[1137] L 1 、X 1 and Q 1 are as defined in any one of numbered paragraphs (99) to (101);

[1138] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1139] all other groups are as defined in any numbered paragraph as appearing above.

[1140] In embodiments of the compounds of formulae I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1141] R 2 as defined in numbered paragraph (6);

[1142] R 4 as defined in numbered paragraph (15);

[1143] R 7 as defined in numbered paragraph (27);

[1144] n as defined in numbered paragraph (30);

[1145] R 8 as defined in numbered paragraph (39);

[1146] R 13 as defined in numbered paragraph (74);

[1147] L 1 、X 1 and Q 1 as defined in numbered paragraph (100);

[1148] R 15 as defined in any one of numbered paragraphs (107); and

[1149] all other groups as defined in any numbered paragraph as appears above.

[1150] In embodiments of the compounds of Formulas I-IV, I-V, I-VI, I-VII or I-VIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1151] R 2 as defined in numbered paragraph (6);

[1152] R 4 as defined in numbered paragraph (17);

[1153] R 7 as defined in numbered paragraph (29);

[1154] n as defined in numbered paragraph (30);

[1155] R 8 as defined in numbered paragraph (39);

[1156] R 13 as defined in numbered paragraph (75);

[1157] L 1 、X 1 and Q 1 as defined in numbered paragraph (101);

[1158] R 15 as defined in any one of numbered paragraphs (108); and

[1159] all other groups as defined in any numbered paragraph as appears above.

[1160] In embodiments of a compound of Formula I-IV, I-V, I-VI, I-VII, I-VIII or I-VIIIa or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1161] R 2 as defined in numbered paragraph (6);

[1162] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1163] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1164] n is as defined in numbered paragraph (30);

[1165] R 8 as defined in numbered paragraph (39);

[1166] R 13 as defined in numbered paragraph (74), (75) or (123) to (125);

[1167] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[1168] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1169] All other groups are as defined in any numbered paragraph as they appear above.

[1170] In embodiments of a compound of Formula I-IV, I-V, I-VI, I-VII, I-VIII or I-VIIIa or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1171] R 2 as defined in numbered paragraph (6);

[1172] R 4 as defined in numbered paragraph (15);

[1173] R 7 as defined in numbered paragraph (27);

[1174] n is as defined in numbered paragraph (30);

[1175] R 8 as defined in numbered paragraph (39);

[1176] R 13 as defined in numbered paragraph (74) or (123);

[1177] L 1 、X 1 and Q 1 as defined in numbered paragraph (100) or (134);

[1178] R 15 as defined in any of numbered paragraphs (107); and

[1179] all other groups as defined in any of the numbered paragraphs appearing above.

[1180] In embodiments of the compounds of Formulas I-IV, I-V, I-VI, I-VII, I-VIII or I-VIIIa, or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1181] R 2 as defined in numbered paragraph (6);

[1182] R 4 as defined in numbered paragraph (17);

[1183] R 7 as defined in numbered paragraph (29);

[1184] n is as defined in numbered paragraph (30);

[1185] R 8 as defined in numbered paragraph (39);

[1186] R 13 as defined in numbered paragraph (75) or (125);

[1187] L 1 、X 1 and Q 1 as defined in numbered paragraph (134) or (135);

[1188] R 15 as defined in any of numbered paragraphs (108); and

[1189] all other groups as defined in any of the numbered paragraphs appearing above.

[1190] In a particular group of compounds of the invention, the compounds have a structure according to Formula I-IX (which is a sub-definition of Formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1191]

[1192] wherein

[1193] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in paragraph (56) above; and

[1194] n, m 1 、R 1 、R 2 、R 3 、R 4 、R 7 and R 9 and any related subunits are as defined in any numbered paragraph above where they appear.

[1195] In a specific group of compounds of the present invention, the compounds have a structure according to formula I-X (which is a sub - definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1196]

[1197] wherein

[1198] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in paragraph (68) above; and

[1199] n, m 1 、R 1 、R 2 、R 3 、R 4 、R 7 and R 9 and any related subunits are as defined in any numbered paragraph above where they appear.

[1200] In a specific group of compounds of the present invention, the compounds have a structure according to formula I-Xa (which is a sub - definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1201]

[1202] wherein

[1203] R 10 is -NR 11 R 12 and R 11 and R12 as defined in the above paragraph (122); and

[1204] n, m 1 , R 1 , R 2 , R 3 , R 4 , R 7 and R 9 , and any related subunits as defined in any numbered paragraph as above appeared.

[1205] In embodiments of the compounds of Formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1206] R 1 and R 3 are defined as in any one of numbered paragraphs (3) to (4);

[1207] m 1 is defined as in numbered paragraph (41) or (42);

[1208] R 2 is defined as in numbered paragraph (5) or (6);

[1209] R 4 is defined as in any one of numbered paragraphs (10) to (17);

[1210] R 7 is defined as in any one of numbered paragraphs (27) to (29);

[1211] n is defined as in numbered paragraph (30); and

[1212] all other groups are defined as in any numbered paragraph as above appeared.

[1213] In embodiments of the compounds of Formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1214] R 1 and R 3 are defined as in any one of numbered paragraphs (3) to (4);

[1215] m 1 is defined as in numbered paragraph (41) or (42);

[1216] R 2 is defined as in numbered paragraph (5) or (6);

[1217] R 4 is defined as in any one of numbered paragraphs (13) to (17);

[1218] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1219] n as defined in numbered paragraph (30);

[1220] R 9 as defined in any one of numbered paragraphs (46) to (50);

[1221] R 13 as defined in numbered paragraph (74) or (75);

[1222] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1223] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1224] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1225] All other groups are as defined in any numbered paragraph as appears above.

[1226] In embodiments of the compounds of Formulas I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1227] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[1228] m 1 as defined in numbered paragraph (41) or (42);

[1229] R 2 as defined in numbered paragraph (5) or (6);

[1230] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1231] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1232] n as defined in numbered paragraph (30);

[1233] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1234] R 13as defined in numbered paragraph (74) or (75);

[1235] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1236] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1237] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1238] All other groups are as defined in any numbered paragraph as appears above.

[1239] In embodiments of the compounds of Formulas I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1240] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[1241] m 1 as defined in numbered paragraph (41) or (42);

[1242] R 2 as defined in numbered paragraph (5) or (6);

[1243] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1244] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1245] n is as defined in numbered paragraph (30);

[1246] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1247] R 13 as defined in numbered paragraph (74) or (75);

[1248] L 1 as defined in any one of numbered paragraphs (81) to (93);

[1249] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1250] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1251] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1252] All other groups are as defined in any numbered paragraph as appears above.

[1253] In embodiments of the compounds of formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1254] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[1255] m 1 as defined in numbered paragraph (41) or (42);

[1256] R 2 as defined in any one of numbered paragraphs (5) or (6);

[1257] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1258] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1259] n is as defined in numbered paragraph (30);

[1260] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1261] R 13 as defined in numbered paragraph (74) or (75);

[1262] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1263] X 1 as defined in any one of numbered paragraphs (88) to (89);

[1264] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[1265] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1266] All other groups are as defined in any numbered paragraph as appears above.

[1267] In embodiments of the compounds of Formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1268] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[1269] m 1 is as defined in numbered paragraph (41) or (42);

[1270] R 2 is as defined in numbered paragraph (6);

[1271] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[1272] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[1273] n is as defined in numbered paragraph (30);

[1274] R 9 is as defined in any one of numbered paragraphs (48) to (50);

[1275] R 13 is as defined in numbered paragraph (74) or (75);

[1276] L 1 is as defined in any one of numbered paragraphs (81) to (83);

[1277] X 1 is as defined in any one of numbered paragraphs (88) to (89);

[1278] Q 1 is as defined in any one of numbered paragraphs (95) to (96);

[1279] R 15 is as defined in any one of numbered paragraphs (105) to (108); and

[1280] all other groups are as defined in any numbered paragraph as they appear above.

[1281] In embodiments of the compounds of Formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1282] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[1283] m1 as defined in numbered paragraph (41) or (42);

[1284] R 2 as defined in numbered paragraph (6);

[1285] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1286] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1287] n as defined in numbered paragraph (30);

[1288] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1289] R 13 as defined in numbered paragraph (74) or (75);

[1290] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1291] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1292] all other groups as defined in any numbered paragraph as appears above.

[1293] In embodiments of the compounds of formulae I-IX or I-X or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1294] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[1295] m 1 as defined in numbered paragraph (41) or (42);

[1296] R 2 as defined in numbered paragraph (6);

[1297] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1298] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1299] as defined in numbered paragraph (30);

[1300] R 13 as defined in numbered paragraph (74) or (75);

[1301] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1302] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1303] all other groups are as defined in any numbered paragraph as appears above.

[1304] In embodiments of the compounds of formulae I-IX or I-X or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1305] R 1 and R 3 are as defined in any one of numbered paragraphs (3) to (4);

[1306] m 1 is as defined in numbered paragraph (41) or (42);

[1307] R 2 is as defined in numbered paragraph (6);

[1308] R 4 is as defined in any one of numbered paragraphs (15) to (17);

[1309] R 7 is as defined in any one of numbered paragraphs (27) to (29);

[1310] n is as defined in numbered paragraph (30);

[1311] R 13 is as defined in numbered paragraph (74) or (75);

[1312] L 1 、X 1 and Q 1 are as defined in any one of numbered paragraphs (99) to (101);

[1313] R 15 is as defined in any one of numbered paragraphs (107) to (108); and

[1314] all other groups are as defined in any numbered paragraph as appears above.

[1315] In embodiments of the compounds of formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1316] R 1 and R 3 are as defined in numbered paragraph (3);

[1317] m 1 is as defined in numbered paragraph (41);

[1318] R 2 is as defined in numbered paragraph (6);

[1319] R 4 is as defined in numbered paragraph (15);

[1320] R 7 is as defined in numbered paragraph (27);

[1321] n is as defined in numbered paragraph (30);

[1322] R 13 is as defined in numbered paragraph (74);

[1323] L 1 、X 1 and Q 1 are as defined in numbered paragraph (100);

[1324] R 15 is as defined in numbered paragraph (107); and

[1325] All other groups are as defined in any numbered paragraph as they appear above.

[1326] In embodiments of the compounds of formulae I-IX or I-X or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1327] R 1 and R 3 are as defined in paragraph (4);

[1328] m 1 is as defined in numbered paragraph (42);

[1329] R 2 is as defined in numbered paragraph (6);

[1330] R 4 is as defined in numbered paragraph (17);

[1331] R 7 is as defined in numbered paragraph (29);

[1332] as defined in numbered paragraph (30);

[1333] R 13 as defined in numbered paragraph (75);

[1334] L 1 、X 1 and Q 1 as defined in numbered paragraph (101);

[1335] R 15 as defined in numbered paragraph (108); and

[1336] all other groups as defined in any numbered paragraph as appears above.

[1337] In embodiments of the compounds of Formulas I-IX, I-X or I-Xa or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1338] R 1 and R 3 as defined in any one of numbered paragraphs (3) to (4);

[1339] m 1 as defined in numbered paragraph (41) or (42);

[1340] R 2 as defined in numbered paragraph (6);

[1341] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1342] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1343] n as defined in numbered paragraph (30);

[1344] R 13 as defined in numbered paragraphs (74), (75) or (123) to (125);

[1345] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[1346] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1347] all other groups as defined in any numbered paragraph as appears above.

[1348] In embodiments of the compounds of Formulas I-IX, I-X or I-Xa or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1349] R 1 and R 3 are as defined in numbered paragraph (3);

[1350] m 1 is as defined in numbered paragraph (41);

[1351] R 2 is as defined in numbered paragraph (6);

[1352] R 4 is as defined in numbered paragraph (15);

[1353] R 7 is as defined in numbered paragraph (27);

[1354] n is as defined in numbered paragraph (30);

[1355] R 13 is as defined in numbered paragraph (74) or (123);

[1356] L 1 、X 1 and Q 1 are as defined in numbered paragraph (100) or (134);

[1357] R 15 is as defined in numbered paragraph (107); and

[1358] all other groups are as defined in any numbered paragraph as they appear above.

[1359] In embodiments of the compounds of Formulas I-IX, I-X or I-Xa or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1360] R 1 and R 3 are as defined in paragraph (4);

[1361] m 1 is as defined in numbered paragraph (42);

[1362] R 2 is as defined in numbered paragraph (6);

[1363] R 4 is as defined in numbered paragraph (17);

[1364] R 7as defined in numbered paragraph (29);

[1365] n as defined in numbered paragraph (30);

[1366] R 13 as defined in numbered paragraph (75) or (124);

[1367] L 1 、X 1 and Q 1 as defined in numbered paragraph (134) or (135);

[1368] R 15 as defined in numbered paragraph (108); and

[1369] all other groups are as defined in any numbered paragraph as appears above.

[1370] In one group of specific compounds of the invention, the compound has a structure according to formulae I-XI (which are sub-definitions of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1371]

[1372] wherein

[1373] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in paragraph (56) above; and

[1374] n, m 1 、R 2 、R 4 、R 7 and R 9 and any related subunits are as defined in any numbered paragraph as appears above.

[1375] In one group of specific compounds of the invention, the compound has a structure according to formulae I-XII (which are sub-definitions of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[1376]

[1377] wherein

[1378] R 10 is -NR 11 R 12 and R 11 and R 12 are as defined in paragraph (68) above; and

[1379] n, m 1 , R 2 , R 4 , R 7 and R 9 and any related subunits as defined in any numbered paragraph as set forth above.

[1380] In embodiments of the compounds of Formulas I-XI or I-XII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1381] m 1 as defined in numbered paragraph (41) or (42);

[1382] R 2 as defined in numbered paragraph (5) or (6);

[1383] R 4 as defined in any one of numbered paragraphs (10) to (17);

[1384] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1385] n is as defined in numbered paragraph (30); and

[1386] all other groups are as defined in any numbered paragraph as set forth above.

[1387] In embodiments of the compounds of Formulas I-XI or I-XII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1388] m 1 as defined in numbered paragraph (41) or (42);

[1389] R 2 as defined in numbered paragraph (5) or (6);

[1390] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1391] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1392] n is as defined in numbered paragraph (30);

[1393] R 9 as defined in any one of numbered paragraphs (46) to (50);

[1394] R 13as defined in numbered paragraph (74) or (75);

[1395] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1396] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1397] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1398] All other groups are as defined in any numbered paragraph as appears above.

[1399] In embodiments of the compounds of formulae I-XI or I-XII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1400] m 1 as defined in numbered paragraph (41) or (42);

[1401] R 2 as defined in numbered paragraph (5) or (6);

[1402] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1403] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1404] n is as defined in numbered paragraph (30);

[1405] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1406] R 13 as defined in numbered paragraph (74) or (75);

[1407] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1408] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1409] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1410] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1411] All other groups are as defined in any numbered paragraph as set forth above.

[1412] In embodiments of the compounds of Formulas I-XI or I-XII or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[1413] m 1 As defined in numbered paragraph (41) or (42);

[1414] R 2 As defined in numbered paragraph (5) or (6);

[1415] R 4 As defined in any one of numbered paragraphs (13) to (17);

[1416] R 7 As defined in any one of numbered paragraphs (27) to (29);

[1417] n is as defined in numbered paragraph (30);

[1418] R 9 As defined in any one of numbered paragraphs (48) to (50);

[1419] R 13 As defined in numbered paragraph (74) or (75);

[1420] R 13a As defined in any one of numbered paragraphs (78) to (79);

[1421] L 1 As defined in any one of numbered paragraphs (81) to (93);

[1422] X 1 As defined in any one of numbered paragraphs (86) to (89);

[1423] Q 1 As defined in any one of numbered paragraphs (93) to (96);

[1424] R 15 As defined in any one of numbered paragraphs (105) to (108); and

[1425] All other groups are as defined in any numbered paragraph as set forth above.

[1426] In embodiments of the compounds of Formulas I-XI or I-XII or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[1427] m 1as defined in numbered paragraph (41) or (42);

[1428] R 2 as defined in numbered paragraph (5) or (6);

[1429] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1430] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1431] n as defined in numbered paragraph (30);

[1432] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1433] R 13 as defined in numbered paragraph (74) or (75);

[1434] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1435] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1436] X 1 as defined in any one of numbered paragraphs (88) to (89);

[1437] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[1438] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1439] all other groups as defined in any numbered paragraph as appears above.

[1440] In embodiments of the compounds of Formulae I-XI or I-XII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1441] m 1 as defined in numbered paragraph (41) or (42);

[1442] R 2 as defined in numbered paragraph (6);

[1443] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1444] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1445] n as defined in numbered paragraph (30);

[1446] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1447] R 13 as defined in numbered paragraph (74) or (75);

[1448] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1449] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1450] X 1 as defined in any one of numbered paragraphs (88) to (89);

[1451] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[1452] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1453] all other groups as defined in any numbered paragraph as appears above.

[1454] In embodiments of the compounds of Formulae I-XI or I-XII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1455] m 1 as defined in numbered paragraph (41) or (42);

[1456] R 2 as defined in numbered paragraph (6);

[1457] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1458] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1459] n as defined in numbered paragraph (30);

[1460] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1461] R 13 as defined in numbered paragraph (74) or (75);

[1462] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1463] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1464] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1465] all other groups as defined in any numbered paragraph as set forth above.

[1466] In embodiments of the compounds of Formulas I-XI or I-XII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1467] m 1 as defined in numbered paragraph (41) or (42);

[1468] R 2 as defined in numbered paragraph (6);

[1469] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1470] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1471] n is as defined in numbered paragraph (30);

[1472] R 13 as defined in numbered paragraph (74) or (75);

[1473] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1474] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1475] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1476] All other groups are as defined in any numbered paragraph as set forth above.

[1477] In embodiments of the compounds of Formulas I-XI or I-XII, or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1478] m 1 As defined in numbered paragraph (41) or (42);

[1479] R 2 As defined in numbered paragraph (6);

[1480] R 4 As defined in any one of numbered paragraphs (15) to (17);

[1481] R 7 As defined in any one of numbered paragraphs (27) to (29);

[1482] n is as defined in numbered paragraph (30);

[1483] R 13 As defined in numbered paragraph (74) or (75);

[1484] R 13a As defined in any one of numbered paragraphs (78) to (79);

[1485] L 1 、X 1 and Q 1 As defined in any one of numbered paragraphs (99) to (101);

[1486] R 15 As defined in any one of numbered paragraphs (107) to (108); and

[1487] All other groups are as defined in any numbered paragraph as set forth above.

[1488] In embodiments of the compounds of Formulas I-XI or I-XII, or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1489] m 1 As defined in numbered paragraph (41);

[1490] R 2 As defined in numbered paragraph (6);

[1491] R 4 As defined in numbered paragraph (15);

[1492] R 7 As defined in numbered paragraph (27);

[1493] as defined in numbered paragraph (30);

[1494] R 13 as defined in numbered paragraph (74);

[1495] R 13a as defined in numbered paragraph (78);

[1496] L 1 、X 1 and Q 1 as defined in numbered paragraph (100);

[1497] R 15 as defined in numbered paragraph (107); and

[1498] all other groups as defined in any numbered paragraph as above appears.

[1499] In embodiments of the compounds of Formulas I-XI or I-XII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1500] m 1 as defined in numbered paragraph (42);

[1501] R 2 as defined in numbered paragraph (6);

[1502] R 4 as defined in numbered paragraph (17);

[1503] R 7 as defined in numbered paragraph (29);

[1504] n as defined in numbered paragraph (30);

[1505] R 13 as defined in numbered paragraph (75);

[1506] R 13a as defined in numbered paragraph (79);

[1507] L 1 、X 1 and Q 1 as defined in numbered paragraph (101);

[1508] R 15 as defined in numbered paragraph (108); and

[1509] all other groups as defined in any numbered paragraph as above appears.

[1510] In a specific group of compounds of formula I, R 6 is as defined in paragraph (109) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 are as defined in any numbered paragraph above where they appear.

[1511] In a specific group of compounds of formula I, R 6 is as defined in paragraph (110) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 are as defined in any numbered paragraph above where they appear.

[1512] In a specific group of compounds of formula I, R 6 is as defined in paragraph (111) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 are as defined in any numbered paragraph above where they appear.

[1513] In a specific group of compounds of formula I, R 6 is as defined in paragraph (112) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 are as defined in any numbered paragraph above where they appear.

[1514] In a specific group of compounds of formula I, R 6 is as defined in paragraph (113) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 are as defined in any numbered paragraph above where they appear.

[1515] In a specific group of compounds of formula I, R 6As defined in paragraph (114) above, and R 1 、R 2 、R 3 、R 4 、n、R 7 、R 8 and R 10 As defined in any numbered paragraph above where they appear.

[1516] In a particular group of compounds of formula I, R 6 As defined in paragraph (115) above, and R 1 、R 2 、R 3 、R 4 、n、R 7 、R 8 and R 10 As defined in any numbered paragraph above where they appear.

[1517] In a particular group of compounds of formula I, R 6 As defined in paragraph (116) above, and R 1 、R 2 、R 3 、R 4 、n、R 7 、R 8 and R 10 As defined in any numbered paragraph above where they appear.

[1518] In a particular group of compounds of formula I, R 6 As defined in paragraph (117) above, and R 1 、R 2 、R 3 、R 4 、n、R 7 、R 8 and R 10 As defined in any numbered paragraph above where they appear.

[1519] In a particular group of compounds of formula I, R 6 As defined in paragraph (118) above, and R 1 、R 2 、R 3 、R 4 、n、R 7 、R 8 and R 10 As defined in any numbered paragraph above where they appear.

[1520] In a particular group of compounds of formula I, R 6 As defined in paragraph (119) above, and R 1, R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 as defined in any numbered paragraph above

[1521] In a specific group of compounds of formula I, R 6 as defined in paragraph (120) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 as defined in any numbered paragraph above

[1522] In a specific group of compounds of formula I, R 6 as defined in paragraph (121) above, and R 1 , R 2 , R 3 , R 4 , n, R 7 , R 8 and R 10 as defined in any numbered paragraph above

[1523] In a specific group of compounds of the present invention, the compounds have a structure according to formula I-XIII (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[1524]

[1525] wherein R 2 , R 4 and R 10 and any related subunits are as defined in any numbered paragraph above, R 6 as defined in any one of paragraphs (109) to (121) above

[1526] In an embodiment of a compound of formula I-XIII or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, R 6 is as defined in paragraph (109) above

[1527] In an embodiment of a compound of formula I-XIII or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, R 6 is as defined in paragraph (110) above

[1528] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (111) above.

[1529] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (112) above.

[1530] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (113) above.

[1531] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (114) above.

[1532] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (115) above.

[1533] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (116) above.

[1534] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (117) above.

[1535] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (118) above.

[1536] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (119) above.

[1537] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 6 is as defined in paragraph (120) above.

[1538] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R6 As defined in paragraph (121) above.

[1539] In embodiments of the compounds of Formulas I-XIII or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[1540] R 2 As defined in numbered paragraph (5) or (6);

[1541] R 4 As defined in any one of numbered paragraphs (10) to (17);

[1542] R 6 As defined in any one of numbered paragraphs (109) to (114);

[1543] R 7 As defined in any one of numbered paragraphs (27) to (29);

[1544] n is as defined in numbered paragraph (30);

[1545] R 8 As defined in any one of numbered paragraphs (31) to (39);

[1546] R 11 and R 12 As defined in any one of numbered paragraphs (53) to (71); and

[1547] All other groups are as defined in any numbered paragraph as they appear above.

[1548] In embodiments of the compounds of Formulas I-XIII or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[1549] R 2 As defined in numbered paragraph (5) or (6);

[1550] R 4 As defined in any one of numbered paragraphs (13) to (17);

[1551] R 6 As defined in any one of numbered paragraphs (111) to (114);

[1552] R 7 As defined in any one of numbered paragraphs (27) to (29);

[1553] n is as defined in numbered paragraph (30);

[1554] R 8 As defined in any one of numbered paragraphs (34) to (39);

[1555] R 9 as defined in any one of numbered paragraphs (46) to (50);

[1556] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71);

[1557] R 13 as defined in numbered paragraph (74) or (75);

[1558] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1559] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1560] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1561] All other groups are as defined in any numbered paragraph as above that appears.

[1562] In embodiments of the compounds of formulae I - XIII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1563] R 2 as defined in numbered paragraph (5) or (6);

[1564] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1565] R 6 as defined in any one of numbered paragraphs (112) to (114);

[1566] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1567] n is as defined in numbered paragraph (30);

[1568] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1569] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1570] R 11 and R 12 as defined in any one of numbered paragraphs (57) to (71);

[1571] R 13 as defined in numbered paragraph (74) or (75);

[1572] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1573] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1574] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1575] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1576] All other groups are as defined in any numbered paragraph as appears above.

[1577] In embodiments of the compounds of Formulas I - XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1578] R 2 as defined in numbered paragraph (5) or (6);

[1579] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1580] R 6 as defined in any one of numbered paragraphs (112) to (114);

[1581] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1582] n is as defined in numbered paragraph (30);

[1583] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1584] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1585] R 11 and R 12 as defined in any one of numbered paragraphs (61) to (71);

[1586] R 13 as defined in numbered paragraph (74) or (75);

[1587] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1588] L 1 as defined in any one of numbered paragraphs (81) to (93);

[1589] X 1 as defined in any one of numbered paragraphs (86) to (89);

[1590] Q 1 as defined in any one of numbered paragraphs (93) to (96);

[1591] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1592] all other groups as defined in any numbered paragraph as above appears.

[1593] In embodiments of the compounds of formulae I - XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1594] R 2 as defined in paragraph (5) or (6);

[1595] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1596] R 6 as defined in any one of numbered paragraphs (112) to (114);

[1597] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1598] n as defined in paragraph (30);

[1599] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1600] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1601] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71);

[1602] R 13 as defined in paragraph (74) or (75);

[1603] R13a as defined in any one of numbered paragraphs (78) to (79);

[1604] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1605] X 1 as defined in any one of numbered paragraphs (88) to (89);

[1606] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[1607] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1608] all other groups as defined in any numbered paragraph as hereinbefore appearing.

[1609] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1610] R 2 as defined in numbered paragraph (6);

[1611] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1612] R 6 as defined in any one of numbered paragraphs (112) to (114);

[1613] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1614] n is as defined in numbered paragraph (30);

[1615] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1616] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1617] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71);

[1618] R 13 as defined in numbered paragraph (74) or (75);

[1619] R 13aas defined in any one of numbered paragraphs (78) to (79);

[1620] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1621] X 1 as defined in any one of numbered paragraphs (88) to (89);

[1622] Q 1 as defined in any one of numbered paragraphs (95) to (96);

[1623] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1624] all other groups are as defined in any numbered paragraph as above appears.

[1625] In embodiments of the compounds of formulae I-XIII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1626] R 2 as defined in numbered paragraph (6);

[1627] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1628] R 6 as defined in any one of numbered paragraphs (112) to (114);

[1629] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1630] n is as defined in numbered paragraph (30);

[1631] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1632] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1633] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71);

[1634] R 13 as defined in numbered paragraph (74) or (75);

[1635] R 13aas defined in any one of numbered paragraphs (78) to (79);

[1636] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1637] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1638] all other groups as defined in any numbered paragraph as appears above.

[1639] In embodiments of the compounds of formulae I - XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1640] R 2 as defined in numbered paragraph (6);

[1641] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1642] R 6 as defined in any one of numbered paragraphs (113) to (114);

[1643] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1644] n as defined in numbered paragraph (30);

[1645] R 8 as defined in numbered paragraph (39);

[1646] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71);

[1647] R 13 as defined in numbered paragraph (74) or (75);

[1648] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1649] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101);

[1650] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1651] All other groups are defined as in any numbered paragraph as set forth above.

[1652] In embodiments of the compounds of Formulas I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1653] R 2 is defined as in numbered paragraph (6);

[1654] R 4 is defined as in any one of numbered paragraphs (15) to (17);

[1655] R 6 is defined as in any one of numbered paragraphs (113) to (114);

[1656] R 7 is defined as in any one of numbered paragraphs (27) to (29);

[1657] n is defined as in numbered paragraph (30);

[1658] R 8 is defined as in numbered paragraph (39);

[1659] R 11 and R 12 are defined as in any one of numbered paragraphs (70) to (71);

[1660] R 13 is defined as in numbered paragraph (74) or (75);

[1661] R 13a is defined as in any one of numbered paragraphs (78) to (79);

[1662] L 1 、X 1 and Q 1 are defined as in any one of numbered paragraphs (99) to (101);

[1663] R 15 is defined as in any one of numbered paragraphs (107) to (108); and

[1664] All other groups are defined as in any numbered paragraph as set forth above.

[1665] In embodiments of the compounds of Formulas I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1666] R 2 is defined as in numbered paragraph (6);

[1667] R 4 as defined in numbered paragraph (15);

[1668] R 6 as defined in numbered paragraph (113);

[1669] R 7 as defined in numbered paragraph (27);

[1670] n as defined in numbered paragraph (30);

[1671] R 8 as defined in numbered paragraph (39);

[1672] R 11 and R 12 as defined in numbered paragraph (70);

[1673] R 13 as defined in numbered paragraph (74);

[1674] R 13a as defined in numbered paragraph (78);

[1675] L 1 、X 1 and Q 1 as defined in numbered paragraph (99);

[1676] R 15 as defined in numbered paragraph (107); and

[1677] all other groups as defined in any numbered paragraph as they appear above.

[1678] In embodiments of the compounds of Formulas I-XIII or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[1679] R 2 as defined in numbered paragraph (5) or (6);

[1680] R 4 as defined in any one of numbered paragraphs (10) to (17);

[1681] R 6 as defined in any one of numbered paragraphs (109) to (121);

[1682] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1683] n as defined in numbered paragraph (30);

[1684] R 8 as defined in any one of numbered paragraphs (31) to (39);

[1685] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71) or (122); and

[1686] all other groups as defined in any numbered paragraph as appears above.

[1687] In embodiments of the compounds of formulae I - XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1688] R 2 as defined in numbered paragraph (5) or (6);

[1689] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1690] R 6 as defined in any one of numbered paragraphs (111) to (121);

[1691] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1692] n is as defined in numbered paragraph (30);

[1693] R 8 as defined in any one of numbered paragraphs (34) to (39);

[1694] R 9 as defined in any one of numbered paragraphs (46) to (50);

[1695] R 11 and R 12 as defined in any one of numbered paragraphs (53) to (71) or (122);

[1696] R 13 as defined in numbered paragraphs (74), (75) or (123) to (125);

[1697] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1698] X 1 as defined in any one of numbered paragraphs (86) to (89) or (126) to (128);

[1699] Q 1as defined in any one of numbered paragraphs (93) to (96) or (129) to (132); and

[1700] all other groups are as defined in any one of the numbered paragraphs as above.

[1701] In embodiments of the compounds of formulae I - XIII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1702] R 2 as defined in numbered paragraph (5) or (6);

[1703] R 4 as defined in any one of numbered paragraphs (13) to (17);

[1704] R 6 as defined in any one of numbered paragraphs (112) to (121);

[1705] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1706] n is as defined in numbered paragraph (30);

[1707] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1708] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1709] R 11 and R 12 as defined in any one of numbered paragraphs (57) to (71) or (122);

[1710] R 13 as defined in numbered paragraph (74), (75), (124) or (125);

[1711] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1712] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1713] X 1 as defined in any one of numbered paragraphs (86) to (89) or (126) to (128);

[1714] Q 1 as defined in any one of numbered paragraphs (93) to (96) or (130) to (132); and

[1715] All other groups are defined as in any numbered paragraph as set forth above.

[1716] In embodiments of the compounds of Formulas I - XIII or pharmaceutically acceptable salts, hydrates, and / or solvates thereof:

[1717] R 2 is defined as in numbered paragraph (5) or (6);

[1718] R 4 is defined as in any one of numbered paragraphs (13) to (17);

[1719] R 6 is defined as in any one of numbered paragraphs (112) to (121);

[1720] R 7 is defined as in any one of numbered paragraphs (27) to (29);

[1721] n is defined as in numbered paragraph (30);

[1722] R 8 is defined as in any one of numbered paragraphs (36) to (39);

[1723] R 9 is defined as in any one of numbered paragraphs (48) to (50);

[1724] R 11 and R 12 are defined as in any one of numbered paragraphs (61) to (71) or (122);

[1725] R 13 is defined as in numbered paragraph (74), (75), or (123);

[1726] R 13a is defined as in any one of numbered paragraphs (78) to (79);

[1727] L 1 is defined as in any one of numbered paragraphs (81) to (83);

[1728] X 1 is defined as in any one of numbered paragraphs (86) to (89) or (126) to (128);

[1729] Q 1 is defined as in any one of numbered paragraphs (93) to (96) or (131) to (132);

[1730] R 15as defined in any one of numbered paragraphs (105) to (108); and

[1731] All other groups are as defined in any of the numbered paragraphs as they appear above.

[1732] In embodiments of the compounds of Formulas I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1733] R 2 as defined in numbered paragraph (5) or (6);

[1734] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1735] R 6 as defined in any one of numbered paragraphs (112) to (114) or (119) to (121);

[1736] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1737] n is as defined in numbered paragraph (30);

[1738] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1739] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1740] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71) or (122);

[1741] R 13 as defined in numbered paragraph (74), (75) or (123);

[1742] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1743] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1744] X[[ID=q5]] 1 as defined in any one of numbered paragraphs (88) to (89) or (127) to (128);

[1745] Q 1 as defined in any one of numbered paragraphs (95) to (96) or (131) to (132);

[1746] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1747] All other groups are as defined in any numbered paragraph as they appear above.

[1748] In embodiments of the compounds of Formulas I - XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1749] R 2 as defined in numbered paragraph (6);

[1750] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1751] R 6 as defined in any one of numbered paragraphs (112) to (114) or (119) to (121);

[1752] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1753] n is as defined in numbered paragraph (30);

[1754] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1755] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1756] R 11 and R 12 as defined in any one of numbered paragraphs (64) to (71) or (122);

[1757] R 13 as defined in numbered paragraph (74), (75) or (123);

[1758] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1759] L 1 as defined in any one of numbered paragraphs (81) to (83);

[1760] X 1 as defined in any one of numbered paragraphs (88) to (89) or (127) to (128);

[1761] Q 1as defined in any one of numbered paragraphs (95) to (96) or (131) to (132);

[1762] R 15 as defined in any one of numbered paragraphs (105) to (108); and

[1763] all other groups are as defined in any numbered paragraph as above appears.

[1764] In embodiments of the compounds of formulae I - XIII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1765] R 2 as defined in numbered paragraph (6);

[1766] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1767] R 6 as defined in any one of numbered paragraphs (112) to (114) or (119) to (121);

[1768] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1769] n is as defined in numbered paragraph (30);

[1770] R 8 as defined in any one of numbered paragraphs (36) to (39);

[1771] R 9 as defined in any one of numbered paragraphs (48) to (50);

[1772] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71) or (122);

[1773] R 13 as defined in numbered paragraph (74), (75) or (124);

[1774] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1775] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[1776] R 15as defined in any one of numbered paragraphs (105) to (108); and

[1777] All other groups are as defined in any numbered paragraph as above appears.

[1778] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1779] R 2 as defined in numbered paragraph (6);

[1780] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1781] R 6 as defined in any one of numbered paragraphs (113) to (114) or (120) to (121);

[1782] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1783] n is as defined in numbered paragraph (30);

[1784] R 8 as defined in numbered paragraph (39);

[1785] R 11 and R 12 as defined in any one of numbered paragraphs (67) to (71) or (122);

[1786] R 13 as defined in numbered paragraph (74), (75) or (124);

[1787] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1788] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[1789] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1790] All other groups are as defined in any numbered paragraph as above appears.

[1791] In embodiments of the compounds of formulae I-XIII or pharmaceutically acceptable salts, hydrates and / or solvates thereof:

[1792] R 2 as defined in numbered paragraph (6);

[1793] R 4 as defined in any one of numbered paragraphs (15) to (17);

[1794] R 6 as defined in any one of numbered paragraphs (113) to (114) or (120) to (121);

[1795] R 7 as defined in any one of numbered paragraphs (27) to (29);

[1796] n as defined in numbered paragraph (30);

[1797] R 8 as defined in numbered paragraph (39);

[1798] R 11 and R 12 as defined in any one of numbered paragraphs (70) to (71) or (122);

[1799] R 13 as defined in numbered paragraphs (74), (75) or (124);

[1800] R 13a as defined in any one of numbered paragraphs (78) to (79);

[1801] L 1 、X 1 and Q 1 as defined in any one of numbered paragraphs (99) to (101) or (133) to (135);

[1802] R 15 as defined in any one of numbered paragraphs (107) to (108); and

[1803] all other groups as defined in any numbered paragraph as appears above.

[1804] In embodiments of the compounds of formulae I - XIII or their pharmaceutically acceptable salts, hydrates and / or solvates:

[1805] R 2 as defined in numbered paragraph (6);

[1806] R 4 as defined in numbered paragraph (15);

[1807] R 6As defined in numbered paragraph (113);

[1808] R 7 As defined in numbered paragraph (27);

[1809] n as defined in numbered paragraph (30);

[1810] R 8 As defined in numbered paragraph (39);

[1811] R 11 and R 12 As defined in numbered paragraph (122);

[1812] R 13 As defined in numbered paragraph (74) or (125);

[1813] R 13a As defined in numbered paragraph (78);

[1814] L 1 、X 1 and Q 1 As defined in numbered paragraph (134) or (135);

[1815] R 15 As defined in numbered paragraph (107); and

[1816] All other groups are as defined in any numbered paragraph as they appear above.

[1817] Specific compounds of the invention include any compound illustrated in this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following compounds:

[1818] [2,4 - Dihydroxy - 6 - (pyrimidin - 2 - ylmethoxy)phenyl] - pyrrolidin - 1 - yl - methanone;

[1819] [2 - (Cyclopentyloxy) - 4,6 - dihydroxy - phenyl] - pyrrolidin - 1 - yl - methanone;

[1820] (2 - Benzyloxy - 4,6 - dihydroxy - phenyl) - pyrrolidin - 1 - yl - methanone;

[1821] (2 - Benzyloxy - 4,6 - dihydroxy - phenyl) - isoindolin - 2 - yl - methanone;

[1822] (2 - Benzyloxy - 4,6 - dihydroxy - phenyl) - (1 - piperidinyl)methanone;

[1823] (2 - Benzyloxy - 4,6 - dihydroxy - phenyl) - [(3S) - 3 - hydroxypyrrolidin - 1 - yl]methanone;

[1824] (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxypyrrolidin-1-yl]methanone;

[1825] (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxy-1-piperidinyl]methanone;

[1826] (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidinyl]methanone;

[1827] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-pyrrolidin-1-yl-methanone;

[1828] (2-Benzyloxy-3-ethyl-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone;

[1829] [2,4-Dihydroxy-6-(2-pyridinylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;

[1830] [2,4-Dihydroxy-6-[(1R)-1-phenoxy]phenyl]-pyrrolidin-1-yl-methanone;

[1831] [2,4-Dihydroxy-6-[(1R)-1-phenoxy]phenyl]-pyrrolidin-1-yl-methanone;

[1832] [2-[(4-Fluorophenyl)methoxy]-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone;

[1833] [2,4-Dihydroxy-6-[(4-methoxyphenyl)methoxy]phenyl]-pyrrolidin-1-yl-methanone;

[1834] [2,4-Dihydroxy-6-(m-tolylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;

[1835] (2-Benzyloxy-4,6-dihydroxy-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone;

[1836] (2-Benzyloxy-4,6-dihydroxy-phenyl)-(4-methoxyisoindolin-2-yl)methanone;

[1837] [2,4-Dihydroxy-6-(pyrimidin-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;

[1838] 2,4-Dihydroxy-6-(1H-pyrazol-3-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;

[1839] [2,4-dihydroxy-6-(1H-1,2,3-triazol-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;

[1840] (2-benzyloxy-4,6-dihydroxy-phenyl)-(5-bromoisoindolin-2-yl)methanone;

[1841] Methyl 2-(2-benzyloxy-4,6-dihydroxybenzoyl)isoindoline-5-carboxylate;

[1842] (2-benzyloxy-4,6-dihydroxy-phenyl)-(5-methoxyisoindolin-2-yl)methanone;

[1843] (2-benzyloxy-4,6-dihydroxy-phenyl)-(5,6-dimethoxyisoindolin-2-yl)methanone;

[1844] [2,4-dihydroxy-6-(1-phenoxy)phenyl]-isoindolin-2-yl-methanone;

[1845] [2,4-dihydroxy-6-(1-phenoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone;

[1846] [2,4-dihydroxy-6-(1-phenoxy)phenyl]-(5,6-dimethoxyisoindolin-2-yl)methanone;

[1847] (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone;

[1848] 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone;

[1849] 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]methanone;

[1850] 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(pyridin-2-ylmethoxy)phenyl]methanone;

[1851] [4,6-dihydroxy-3-methyl-2-(pyridin-2-ylmethoxy)phenyl]-isoindolin-2-yl-methanone;

[1852] 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(pyridin-2-ylmethoxy)phenyl]methanone;

[1853] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone;

[1854] [2,4-Dihydroxy-6-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone;

[1855] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(4-bromoisoindolin-2-yl)methanone;

[1856] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[4-(hydroxymethyl)isoindolin-2-yl]methanone;

[1857] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[5-[(4-methylpiperazin-1-yl)methyl]isoindolin-2-yl]methanone;

[1858] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;

[1859] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)methanone;

[1860] (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,6-naphthyridin-2-yl)methanone;

[1861] 3,4-Dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone;

[1862] 3,4-Dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone;

[1863] [4,6-Dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;

[1864] [4,6-Dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;

[1865] 3,4-Dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone;

[1866] (2-(Benzyloxy)-4,6-dihydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;

[1867] (4-Aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone;

[1868] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisoindolin-2-yl)methanone;

[1869] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1870] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone;

[1871] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

[1872] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone;

[1873] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone;

[1874] (3,4-Dihydroisoquinolin-2(1H)-yl)(4,6-dihydroxy-3-methyl-2-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)methanone;

[1875] (2-(Benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1876] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(isoindolin-2-yl)methanone;

[1877] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1878] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1879] (S)-(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1880] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)isoindolin-2-yl)methanone;

[1881] (R)-(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1882] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1883] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[1884] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone;

[1885] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone;

[1886] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone;

[1887] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(indolin-1-yl)methanone;

[1888] (2-(Benzyloxy)-4,6-dihydroxyphenyl)(indolin-1-yl)methanone;

[1889] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone;

[1890] (2-(Benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone;

[1891] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone;

[1892] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;

[1893] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone;

[1894] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;

[1895] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide;

[1896] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone;

[1897] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone;

[1898] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone;

[1899] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile;

[1900] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide;

[1901] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-5-carboxamide;

[1902] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide;

[1903] 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide;

[1904] N-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide;

[1905] ((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone;

[1906] (4-(Azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone;

[1907] (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone;

[1908] 1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile;

[1909] (4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;

[1910] (2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;

[1911] (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;

[1912] (2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; and

[1913] (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[1914] The various functional groups and substituents of the compounds of formula (I) or sub-formulas (I-I) to (I-XII) are usually selected such that the molecular weight of the compounds of formula (I) does not exceed 1000. More usually, the molecular weight of the compounds will be less than 900, such as less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, 550 or less.

[1915] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention, which are sufficiently basic, for example, acid addition salts with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonate or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[1916] 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 atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", while those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequence rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. Compounds containing equal proportions of enantiomers are called "racemic compounds".

[1917] The compounds of the present invention may have one or more asymmetric centers; thus, such compounds can be produced in the form of individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th Edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of the racemic form. Some compounds of the present invention may have geometric isomeric centers (E and Z isomers).

[1918] It should be understood that the present invention includes all active enantiomers, diastereomers and geometric isomers and mixtures thereof.

[1919] The present invention also includes the compounds of the invention containing one or more isotopically substituted as defined herein. 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; and O can be in any isotopic form, including 16O and 18O; etc.

[1920] It should also be understood that certain compounds of formula (I) or sub-formulae (I-I) to (I-XII) can exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention includes all such solvated forms having activity.

[1921] It should also be understood that certain compounds of formula (I) or sub-formulae (I-I) to (I-XII) may exhibit polymorphism, and the present invention includes all such forms having activity.

[1922] The compounds of formula (I) or sub-formulae (I-I) to (I-XII) can exist in many different tautomeric forms, and when referring to the compounds of formula (I) or sub-formulae (I-I) to (I-XII), all such forms are included. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all others are included in formula (I) or sub-formulae (I-I) to (I-XII). Examples of tautomeric forms include keto-, enol- and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidoxime, nitroso / oxime, thione / enethiol and nitro / aci-nitro.

[1923]

[1924] Compounds of formula (I) or sub-formulae (I-I) to (I-XII) containing an amine functional group can also form N-oxides. Compounds of formula (I) or sub-formulae (I-I) to (I-XII) containing an amine functional group mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of the nitrogen atoms of tertiary amines or 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, Jerry March's "Advanced Organic Chemistry", 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[1925] Compounds of formula (I) or sub-formulas (I-I) to (I-XII) can be administered in the form of prodrugs, which release the compounds of the present invention in the human or animal body. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. When the compounds of the present invention contain suitable groups or substituents, prodrugs can be formed, and the modifying group can be attached to such group or substituent. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl groups of the compounds of formula (I) or sub-formulas (I-I) to (I-XII), and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino groups of the compounds of formula (I) or sub-formulas (I-I) to (I-XII).

[1926] Accordingly, the present invention includes those compounds of formula (I) or sub-formulas (I-I) to (I-XII) as defined above, when obtained by organic synthesis and when obtained in the human or animal body by cleavage of their prodrugs. Thus, the present invention includes those compounds of formula (I) or sub-formulas (I-I) to (I-XII) produced by organic synthesis methods, and such compounds produced in the human or animal body by metabolism of precursor compounds, i.e., the compounds of formula (I) or sub-formulas (I-I) to (I-XII) can be synthetically produced compounds or metabolically produced compounds.

[1927] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or sub-formulas (I-I) to (I-XII) are drugs based on reasonable medical judgment, which are suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity.

[1928] Various forms of prodrugs have been described, for example, in the following documents: -

[1929] a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

[1930] b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

[1931] 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);

[1932] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[1933] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[1934] f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

[1935] g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

[1936] h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1937] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or sub-formulae (I-I) to (I-XII) having a carboxyl group are, for example, their in vivo cleavable esters. In vivo cleavable esters of the compounds of formula I or sub-formulae (I-I) to (I-XII) containing a carboxyl group are, for example, pharmaceutically acceptable esters which, when cleaved in the human or animal body, give rise to the parent acid or the parent alcohol. Pharmaceutically acceptable esters suitable for carboxyl groups include (1-6C) alkyl esters such as methyl, ethyl and tert-butyl esters, (1-6C) alkoxymethyl esters such as methoxymethyl ester, (1-6C) alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthalyl esters, (3-8C) cycloalkylcarbonyloxy-(1-6C) alkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolylmethyl esters such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester and (1-6C) alkoxycarbonyloxy-(1-6C) alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

[1938] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or sub-formulae (I-I) to (I-XII) having a hydroxyl group are, for example, their in vivo cleavable esters or ethers. In vivo cleavable esters or ethers of the compounds of formula (I) or sub-formulae (I-I) to (I-XII) containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers which, when cleaved in the human or animal body, give rise to the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxyl groups include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for hydroxyl groups include (1-10C) alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C) alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C)2-carbonyl, 2-dialkylaminoacetyl and 2-carboxyacetyl 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) alkylpiperazin-1-ylmethyl groups. Suitable pharmaceutically acceptable ether-forming groups for hydroxyl groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[1939] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or sub-formulae (I-I) to (I-XII) having a carboxyl group are, for example, their in vivo cleavable amides, for example with amines such as ammonia, 1-4C alkylamines such as methylamine, [(1-4C) alkyl]2 amines 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 their esters.

[1940] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or sub-formulae (I-I) to (I-XII) having an amino group are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, amides formed by (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.

[1941] The in vivo action of the compounds of formula (I) or the compounds of sub-formulae (I-I) to (I-XII) can be exerted in part by one or more metabolites formed in the human or animal body after administration of the compounds of formula (I) or the compounds of sub-formulae (I-I) to (I-XII). As described above, the in vivo action of the compounds of formula (I) or the compounds of sub-formulae (I-I) to (I-XII) can also be exerted by the metabolism of the precursor compounds (prodrugs).

[1942] Although the present invention may relate to any compound or specific group of compounds defined herein by way of optional, preferred or suitable features or in a particular embodiment, the present invention may also relate to any compound or specific group of compounds that explicitly exclude said optional, preferred or suitable features or particular embodiments.

[1943] Suitably, the present invention excludes any single compound that does not have the biological activity defined herein.

[1944] Synthesis

[1945] The compounds of the present invention can be prepared by any suitable technique known in the art. The specific methods for preparing these compounds are further described in the appended examples.

[1946] In the description of the synthetic methods described herein and in any reference synthetic methods used for preparing starting materials, it should be understood that those skilled in the art can select all the proposed reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experiment durations and work-up procedures.

[1947] Those skilled in the art of organic synthesis can understand that the functions of different parts of the molecule must be adapted to the reagents and reaction conditions used.

[1948] It should be understood that in the process of synthesizing the compounds of the present invention in the methods defined herein, or in the process of synthesizing certain starting materials, it may be necessary to protect certain substituents to prevent them from undergoing unwanted reactions. A skilled chemist will understand when such protection is required and how to place such protecting groups in the appropriate positions and then remove them.

[1949] 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; (Publisher: John Wiley & Sons). The protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist that is suitable for removing the protecting group in question, and such a method is chosen so as to effect the removal of the protecting group with minimal interference to other groups in the molecule.

[1950] Thus, if the reactants include groups such as, for example, amino, carboxyl or hydroxyl groups, it may be necessary to protect such groups in some of the reactions mentioned herein.

[1951] For example, suitable protecting groups for an amino or alkylamino group are, for example, acyl groups such as alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the above-mentioned protecting groups must vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl group or an alkoxycarbonyl group or an aroyl group can be removed by hydrolysis, for example, with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as tert-butoxycarbonyl can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as benzyloxycarbonyl can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or with hydrazine.

[1952] Suitable protecting groups for a hydroxyl group are, for example, acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above-mentioned protecting groups will necessarily vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as benzyl can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[1953] Suitable protecting groups for carboxyl groups are, for example, esterifying groups such as methyl or ethyl which can be removed by hydrolysis with a base such as sodium hydroxide, or tert-butyl which can be removed by treatment with an acid such as an organic acid like trifluoroacetic acid, or benzyl which can be removed by hydrogenation, for example, over a catalyst such as palladium on carbon.

[1954] Resins can also be used as protecting groups.

[1955] The method for synthesizing the compounds of formula (I) or sub-formulas (I-I) to (I-XII) will vary according to the nature of R 1 、R 2 、R 3 、R 4 、R 6 and R 10 and any substituents or subunits associated therewith. Suitable methods for preparing them are further described in the accompanying examples.

[1956] Once the compounds of formula (I) or sub-formulas (I-I) to (I-XII) are synthesized by any of the methods defined herein, the method can further include additional steps:

[1957] (i) Removing any protecting groups present;

[1958] (ii) Converting the compound of formula (I) into another compound of formula (I);

[1959] (iii) Forming its pharmaceutically acceptable salts, hydrates or solvates; and / or

[1960] (iv) Forming its prodrugs.

[1961] An example of (ii) above is when a compound of formula (I) is synthesized and then one or more of the groups R 1 、R 2 、R 3 、R 4 、R 6 and R 10 can be further reacted to change the nature of the group and provide an alternative compound of formula (I).

[1962] The resulting compounds of formula (I) or sub-formulas (I-I) to (I-XII) can be isolated and purified using techniques well known in the art.

[1963] The compounds of formula (I) can be synthesized by the synthetic routes shown in the following Examples section.

[1964] Biological Activity

[1965] The bioassays described in the Examples section herein can be used to measure the pharmacological effects of the compounds of the present invention.

[1966] Although, as expected, the pharmacological properties of the compounds of formula (I) vary with structural changes, it has been found that the compounds of the present invention are active in the PMS2 in vitro assay and, in some cases, in the MLH1 in vitro assay described in the Examples section.

[1967] Pharmaceutical Compositions

[1968] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[1969] The compositions of the present invention can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., finely divided powders or liquid aerosols), suitable for administration by insufflation (e.g., as a finely divided powder) or suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular injection, or as a suppository for rectal administration).

[1970] The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients known in the art. Thus, compositions for oral use can contain, for example, one or more colorants, sweeteners, flavorants and / or preservatives.

[1971] An effective amount of the compound of the present invention for treatment is an amount sufficient to treat or prevent the proliferative conditions referred to herein, slow its progression and / or alleviate the symptoms associated with the condition.

[1972] The amount of the active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the particular route of administration. For example, a preparation for oral administration to humans typically contains, for example, from 0.5 mg to 0.5 g of the active agent (more suitably from 0.5 to 100 mg, such as from 1 to 30 mg), admixed with a suitable and convenient amount of excipients which can make up from about 5% to about 98% of the total weight of the composition.

[1973] In accordance with well-known medical principles, the dosage size of the compounds of formula I for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration.

[1974] When using the compounds of the present invention for therapeutic or prophylactic purposes, the compounds are generally administered so as to obtain a daily dose in the range, for example, of from 0.1 mg / kg to 75 mg / kg body weight (administered in divided doses if desired). Generally, when the parenteral route is employed, lower doses will be administered. Thus, for example, for intravenous or intraperitoneal administration, doses in the range of from 0.1 mg / kg to 30 mg / kg body weight are typically used. Similarly, for inhaled administration, doses in the range of, for example, from 0.05 mg / kg to 25 mg / kg body weight are used. Oral administration is also suitable, particularly in the form of tablets. Typically, unit dosage forms will contain from about 0.5 mg to 0.5 g of the compound of the present invention.

[1975] Therapeutic Uses and Applications

[1976] The present invention provides compounds useful as inhibitors of MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities).

[1977] Accordingly, the compounds of formula (I) or pharmaceutically acceptable salts thereof have potential therapeutic utility in a variety of disease states in which inhibition of MLH1 and / or PMS2 activity is beneficial.

[1978] Accordingly, the present invention provides a method of treating a disease or disorder in which inhibition of MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities) is beneficial to a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[1979] The present invention provides a method of inhibiting MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities) in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.

[1980] The present invention provides a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[1981] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[1982] 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.

[1983] 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.

[1984] 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 disease.

[1985] 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 specific embodiment, the cancer is a human cancer. In a specific 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.

[1986] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities). Preferably, a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting PMS2 activity is provided; most preferably, for inhibiting PMS2 and MLH1 activities.

[1987] 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 inhibiting MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities) is beneficial.

[1988] The present 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 use in the treatment of a proliferative disease.

[1989] The present 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 use in the treatment of cancer.

[1990] The present 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 use in inhibiting MLH1 and / or PMS2 activity (such as MLH1 activity or PMS2 activity or MLH1 and PMS2 activities).

[1991] The present 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 treating a disease or disorder, wherein inhibition of MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activities) is beneficial.

[1992] The terms "proliferative disorder", "proliferative condition" and "proliferative disease" are used interchangeably herein and refer to an undesired or uncontrolled cell proliferation of unwanted or abnormal cells, such as a tumor or hyperplastic growth, whether in vitro or in vivo.

[1993] In the foregoing aspects of the present invention, the proliferative disease is suitably cancer, and the cancer is suitably human cancer. In particular, the compounds of the present invention will be useful for treating any cancer in which mismatch repair inhibition is beneficial. Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendiceal cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, biliary tract cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney syndrome, central nervous system tumor, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor - GIST, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor (e.g., tumors of the gastrointestinal tract, lung or pancreas), neurofibromatosis type 1 and type 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi sarcoma 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, Waldenstrom macroglobulinemia, Werner syndrome, Wilms tumor, and xeroderma pigmentosum).Particular cancers of interest include blood cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastroesophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, central nervous system cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[1994] The compounds of the invention can also be used to treat trinucleotide diseases.

[1995] Accordingly, another aspect of the invention provides a method for treating a trinucleotide disorder (e.g., Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar ataxia (SCA)) in a patient in need of such treatment, the method comprising administering to the 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.

[1996] According to another aspect of the invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for treating a trinucleotide disorder. In a specific embodiment, the trinucleotide 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 ataxia (SCA).

[1997] According to another 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 treating a trinucleotide disorder. In a specific embodiment, the trinucleotide 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 ataxia (SCA).

[1998] Routes of Administration

[1999] The compounds of the invention or pharmaceutical compositions comprising these compounds can be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the site of desired action).

[2000] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patch, plaster, etc.); transmucosal (including, e.g., by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, e.g., by injection, including intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by subcutaneous or intramuscular implant reservoir or depot, e.g..

[2001] Combination Therapies

[2002] The compounds of the present invention can be administered as a single therapy, or in addition to the compounds of the present invention, can also include conventional surgery or radiotherapy or chemotherapy or targeted agents. Such chemotherapy or targeted agents can include one or more of the following categories:

[2003] (i) Anti - proliferative / anti - tumor drugs for medical oncology and their combinations, such as, but not limited to, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as 5 - fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); anti - tumor antibiotics (e.g., anthracycline antibiotics such as adriamycin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin - C, dactinomycin, and mithramycin); anti - mitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and docetaxel, and multi - kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

[2004] (ii) Cell growth inhibitors, such as, but not limited to, anti - estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti - androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), steroid hormones, including progestins (e.g., medroxyprogesterone acetate) and corticosteroids (e.g., dexamethasone, prednisone, and prednisolone), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and 5 - reductase inhibitors, e.g., finasteride;

[2005] (iii) Anti-invasive agents, such as but not limited to c-Src kinase family inhibitor 4-(6-chloro-2,3-methylenedioxyaniline)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), bosutinib (SKI-606) and metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitor or heparanase antibody;

[2006] (iv) Inhibitors of growth factor function, such as but not limited to growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin TM, anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033)), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib (BAY 43-9006), tipifarnib (R115777), and lonafarnib (SCH66336)), cell signaling inhibitors through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[2007] (v) Anti-angiogenic agents, such as but not limited to those drugs that inhibit the action of vascular endothelial growth factor, [such as anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ) and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), and pazopanib (GW 786034).

[2008] (vi) Vascular damaging agents, such as but not limited to combretastatin A4 and the compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213;

[2009] (vii) Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan;

[2010] (viii) Antisense therapies, such as but not limited to those directed against the targets listed above, such as ISIS 2503, an anti-ras antisense;

[2011] (ix) Immunotherapies, including for example cancer vaccines, antibodies, viruses (oncolytic viruses) and small molecule or cell therapies to increase the immunogenicity of a patient's tumor cells and / or promote a cell-mediated anti-tumor response. Such therapies can include but are not limited to OX40 agonists, cGAS-STING agonists, ENPP1 inhibitors, CD38 inhibitors, TBK1 inhibitors, A2a receptor antagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, arginase inhibitors, BTK inhibitors and bromodomain inhibitors; transduction with a microbial vector of a cancer antigen, direct transduction of a cancer antigen into antigen-presenting cells, treatment with immune cells specific for a cancer antigen (such as CAR-T), treatment with antibodies, antibody fragments and antibody-drug conjugates that enable the immune system to recognize tumor cells.

[2012] Such combination therapy can be achieved by administering the individual components of the therapy simultaneously, sequentially or separately. Such combination products use the compounds of the invention in the dosage ranges described above and other pharmaceutically active agents in their approved dosage ranges.

[2013] According to this aspect of the invention, there is provided a combination for treating cancer (such as cancer involving solid tumors), which comprises a compound of the invention or a pharmaceutically acceptable salt or solvate thereof as defined above, and an anti-tumor agent.

[2014] According to this aspect of the invention, there is provided a combination for treating a proliferative disease such as cancer (such as cancer involving solid tumors), which comprises a compound of the invention or a pharmaceutically acceptable salt or solvate thereof as defined above, and any one of the anti-tumor agents listed above.

[2015] In another aspect of the invention, there is provided a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in combination with another anti-tumor agent for treating cancer, said another anti-tumor agent being optionally selected from one of those listed above.

[2016] In another aspect of the invention, there is provided a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in combination with a tyrosine kinase inhibitor for treating cancer, said tyrosine kinase inhibitor being optionally selected from one of those listed above.

[2017] In this text, when the term "combination" is used, it should be understood to mean administration simultaneously, separately, or sequentially. In one aspect of the invention, "combination" means simultaneous administration. In another aspect of the invention, "combination" means separate administration. In yet another aspect of the invention, "combination" means sequential administration. When administered sequentially or separately, the delayed administration of the second component should not result in the loss of the beneficial effects of the combination.

[2018] According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, in combination with an anti-tumor agent (optionally selected from one of those listed above) and a pharmaceutically acceptable diluent or carrier.

[2019] Combination Therapies with Immunomodulatory Therapies

[2020] immune checkpoint inhibitor

[2021] Immune checkpoint proteins present on immune cells and / or cancer cells [such as 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 important roles in regulating anti-tumor immune responses. Inhibitors of these immune checkpoint proteins (such as CTLA4, LAG3, PD1, PD-L1, TIM-3, and / or TIGIT inhibitors) promote anti-tumor immune responses and can be used to effectively treat certain forms of cancer.

[2022] immune stimulant

[2023] Monoclonal antibodies, bispecific antibodies, recombinant ligands, and small molecule therapeutic agents that bind to stimulatory receptors on immune cells can promote effective anti-tumor responses. Such receptors may be involved in cell-to-cell contact, such as contact between tumor cells and immune cells or between two types of immune cells, and other receptors may bind to soluble factors that stimulate immune responses. In one such embodiment, the antibody, bispecific, recombinant protein, or small molecule therapeutic agent can activate stimulatory receptors, including but not limited to 4-1BB, OX40, cGAS-STING, CD27, CD40, and DR3, which enhance anti-tumor immunity.

[2024] Modulators of antigen processing can promote the presentation of neoantigen peptides on the cell surface, thereby enhancing an effective anti-tumor response. In one such embodiment, inhibitors of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 can stimulate anti-tumor immunity.

[2025] In one aspect, the present invention relates to a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immune stimulant as defined herein or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease.

[2026] In another aspect, the present 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 immune stimulant as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a proliferative disease.

[2027] In another aspect, the present invention relates to a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immune stimulant as defined herein or a pharmaceutically acceptable salt thereof.

[2028] In another aspect, the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease, wherein the compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with an immune checkpoint inhibitor or immune stimulant or a pharmaceutically acceptable salt thereof.

[2029] In another aspect, the present invention relates to an immune checkpoint inhibitor or immune stimulant or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease, wherein the immune checkpoint inhibitor is for administration simultaneously, separately or sequentially with a compound as defined herein or a pharmaceutically acceptable salt thereof.

[2030] In another aspect, the present invention relates to the use of a compound as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a proliferative disease, wherein the medicament is for administration simultaneously, separately or sequentially with an immune checkpoint inhibitor or immune stimulant or a pharmaceutically acceptable salt thereof.

[2031] In another aspect, the present invention relates to the use of an immune checkpoint inhibitor or immune stimulant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a proliferative disease, wherein the medicament is for administration simultaneously, separately or sequentially with a compound as defined herein or a pharmaceutically acceptable salt thereof.

[2032] In another aspect, the present invention relates to a method for treating a proliferative disease, the method comprising administering, sequentially, separately or simultaneously, to a subject in need thereof, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as defined herein and an immune checkpoint inhibitor or an immune stimulant or a pharmaceutically acceptable salt thereof as defined herein.

[2033] Any immune checkpoint inhibitor or immune stimulant can be used in the combination therapy defined herein.

[2034] In one embodiment, the immune stimulant is selected from 4-1BB stimulant, OX40 stimulant, CD27 stimulant, CD40 stimulant and DR3 stimulant. In another embodiment, the immune checkpoint inhibitor is selected from PD1 inhibitor, PD-L1 inhibitor, LAG3 inhibitor, CTLA-4 inhibitor, TIM-3 inhibitor and / or TIGIT inhibitor. In a specific embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[2035] PD-1 is a cell surface receptor protein present on immune cells such as T cells. PD-1 plays an important role in downregulating the immune system and promoting self-tolerance by inhibiting T cell activation. The PD-1 protein is an immune checkpoint that prevents autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) of antigen-specific T cells in lymph nodes while reducing apoptosis of regulatory T cells (anti-inflammatory inhibitory T cells).

[2036] PD-1 thus inhibits the immune system. This can prevent autoimmune diseases but can also prevent the immune system from killing cancer cells.

[2037] 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 thus the role of PD1 in cancer immune evasion is clear. Monoclonal antibodies against PD-1 that enhance the immune system have been approved or are under development for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibiting the interaction between PD-1 and PD-L1 can enhance T cell responses in vitro and mediate preclinical antitumor activity. This is so-called immune checkpoint blockade.

[2038] Examples of drugs targeting PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including cutaneous melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck cancer, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. Drugs under development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics), and MEDI-0680 (MedImmune).

[2039] Drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell carcinoma (Merkel cell skin cancer). They are also being studied for use in treating other types of cancer.

[2040] Examples of LAG3 inhibitors include BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART that binds PD-1 and LAG-3), GSK2831781, and LAG525.

[2041] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab.

[2042] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Eli Lilly).

[2043] Examples of TIGIT inhibitors include tirzepatide (MTIG7192A; RG6058; Genentech / Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207 (Bristol Myers Squibb), ASP8374 (Astellas Pharma; Potenza Therapeutics).

[2044] In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding to 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, Tirzepatide (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, and / or ASP8374 or a pharmaceutically acceptable salt or solvate thereof.

[2045] Combination Therapy with DNA Damage Response Modulators

[2046] The compounds of the present invention are particularly suitable for use in combination with drugs used as DNA damage response regulators, such as PARP inhibitors, ATM inhibitors, and ATR inhibitors.

[2047] In one aspect, the present invention relates to a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof, and a DNA damage response regulator (such as a PARP inhibitor, an ATM inhibitor, and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof, for use in the treatment of proliferative diseases.

[2048] In another aspect, the present 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 regulator (such as a PARP inhibitor, an ATM inhibitor, and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of proliferative diseases.

[2049] In another aspect, the present invention relates to a method for treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof, and a DNA disruption response regulator as defined herein (such as a PARP inhibitor, an ATM inhibitor, and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[2050] In another aspect, the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of proliferative diseases, wherein the compound or the pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with a DNA disruption response regulator (such as a PARP inhibitor, an ATM inhibitor, and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[2051] In another aspect, the present invention relates to the use of a compound as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a proliferative disease, wherein the medicament is for simultaneous, separate or sequential administration with a DNA-damaging response modulator (such as a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[2052] In another aspect, the present invention relates to a method for treating a proliferative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof and a DNA damage response modulator (such as a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof, sequentially, separately or simultaneously.

[2053] Any DNA damage response modulator (such as a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) can be used in the combination therapy defined herein.

[2054] Probe Compounds

[2055] The present invention also relates to novel probe molecules formed by linking a compound of the present invention as defined herein to a detection moiety via a linker group. The present invention also relates to methods for synthesizing these novel probe molecules and their use in assays and screens for determining the binding of a test molecule to the ATP-binding site of a target protein (such as mismatch repair (MMR) component proteins PMS2 and MLH1), or for determining the location and / or amount of such a target protein in a biological sample.

[2056] In one aspect, the present invention provides a probe compound comprising a compound of formula (I) or sub-formulas (I-I) to (I-XII) or a salt thereof bound to a detection moiety via a linker.

[2057] In another aspect, the present invention provides a method for synthesizing a probe compound or a salt thereof as defined herein.

[2058] In another aspect, the present invention provides the use of a probe compound or a salt thereof as defined herein in a displacement assay to determine the binding affinity of a test molecule for the ATP-binding site of a target protein. In one embodiment, the target protein is selected from MLH1, PMS2 or HSP90. In a particular embodiment, the target protein is MLH1 or PMS2.

[2059] In another aspect, the present invention provides a probe compound or a salt thereof for use in a displacement assay to determine the binding affinity of a test molecule for the ATP-binding site of a target protein. In one embodiment, the target protein is selected from MLH1, PMS2 or HSP90. In a particular embodiment, the target protein is MLH1 or PMS2.

[2060] In another aspect, the present invention provides an assay for determining the binding affinity of a test molecule to the ATP binding site of a target protein, the assay comprising:

[2061] (i) incubating the test molecule with the target protein in the presence of a probe compound or a salt thereof as defined herein; and

[2062] (ii) determining whether the probe compound is displaced from the ATP binding site of the target protein.

[2063] In one embodiment, the target protein is selected from MLH1, PMS2 or HSP90. In a particular embodiment, the target protein is MLH1 or PMS2.

[2064] In another aspect, the present invention provides a method for determining the binding affinity of a test molecule to the ATP binding site of a target protein, the assay comprising:

[2065] (i) incubating the test molecule with the target protein in the presence of a probe compound or a salt thereof as defined herein; and

[2066] (ii) determining whether the probe compound is displaced from the ATP binding site of the target protein.

[2067] In another aspect, the present invention provides an assay for determining the location and / or quantity of a target protein present in a biological sample, the assay comprising:

[2068] (i) contacting the biological sample with a probe compound or a salt thereof as defined herein; and

[2069] (ii) determining the location and / or quantity of the compound of formula I present in the sample by detecting the location and / or intensity of the detection moiety of the compound present in the biological sample.

[2070] Suitably, the present invention relates to a probe compound of formula B or a salt thereof:

[2071]

[2072] Wherein:

[2073] R 1 、R 2 、R 3 、R 4 and R 6 are each as defined herein;

[2074] R 10 is a group R 10 connected to L as defined herein;

[2075] L is a linker; and

[2076] Q is a detection moiety.

[2077] The linker group L can be any suitable linker moiety that attaches the detection moiety Q to the remainder of the probe compound of formula B.

[2078] Suitably, the linker group L has a length of from 3 to 30 atoms, more suitably from 4 to 20 atoms, even more suitably from 5 to 18 atoms. In a particular set of probe compounds of formula I or II as defined herein, L has a length of from 5 to 12 atoms.

[2079] The detection moiety Q can be any moiety capable of detecting and quantifying the probe compound of formula I. As further described below, the probe compounds of formula I as defined herein are designed for displacement assays, whereby the ability of a test compound to displace the probe compound of formula I from the ATP-binding site of a target protein (such as 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 is readily detectable and quantifiable. In some cases, the detection moiety Q enables any probe compound of formula I that has been displaced (i.e., "unbound") from the ATP-binding site of the target protein to be detected and quantified. In certain embodiments of the present invention, this can be achieved by collecting any displaced or "unbound" compound of formula I from the test sample and assaying the sample to determine how much unbound probe compound is present. This in turn will indicate how much of the probe compound present in the sample has been displaced by the test compound.

[2080] Thus, it should 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 the probe compound of formula I present in a sample. Those skilled in the art will be able to select a suitable detection moiety Q and a suitable method for detecting and quantifying the amount of the compound of formula I in a sample, particularly the amount of the probe compound of formula I displaced by the test compound from the ATP-binding site of the target protein.

[2081] 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.

[2082] In embodiments where the detection moiety Q is an oligonucleotide, biomolecule, molecular sensor, protein, or peptide, any suitable technique known in the art can be utilized to detect and quantify the amount of oligonucleotide, biomolecule, molecular sensor, protein, or peptide present. For example, a fluorescently labeled second probe can be used that is capable of specifically binding to the detection moiety Q of the probe compound of Formula I, and once any excess second probe is removed, the amount of binding of the second probe to the detection moiety Q of the compound of Formula I can be detected and quantified, thereby enabling determination of the amount of the probe compound of Formula I.

[2083] For example, if Q is an oligonucleotide, a second probe having a suitable detectable label (e.g., a fluorophore or a 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 (and suitably the amount of probe compound displaced from the ATP binding site of the target protein by the test compound). Similarly, if Q is a protein or peptide, the second probe can be an antibody capable of selectively binding to the protein or peptide and a suitable detectable label, such as a fluorophore or a radiolabel.

[2084] More preferably, the detection moiety Q is a fluorophore. In this case, the compounds of Formula I can be used in fluorescence polarization assays. In one 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 another 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, Cy-5B, Cy-3B, fluorescein, BODIPY TMR, TAMRA, Oregon Green 488, Oregon Green 514, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red.

[2085] 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, e.g., acid addition salts with, for example, 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. Additionally, suitable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases.

[2086] The present invention also includes the probe compounds of the present invention as defined herein, which comprise one or more isotope substitutions. For example, H can be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C can be in any isotopic form, including 12 C, 13 C, and 14 C; and O can be in any isotopic form, including 16 O and 18 O, and so on.

[2087] It should also be understood that certain probe compounds of formula (I) can exist in solvated and non-solvated forms, such as the hydrated form.

[2088] It should also be understood that certain probe compounds of formula (I) may exhibit polymorphism, and the present invention includes all such polymorphic forms.

[2089] Certain probe compounds of formula (I) can also exist in many different tautomeric forms, and reference to the compounds of formula (I) includes all such forms.

[2090] Synthesis of Probe Compounds

[2091] On the other hand, the present invention provides a method for synthesizing a probe compound of formula B or a salt thereof as defined herein.

[2092] The probe compounds of the present invention can be prepared by any suitable technique known in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[2093] Although specific embodiments of the present invention have been described herein for purposes of reference and illustration, various modifications will be apparent to those skilled in the art without departing from the scope of the present invention as defined by the appended claims. Referring to the drawings, wherein:

[2094] Figure 1 The reaction scheme of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile (Example 82) is shown;

[2095] Figure 2 The reaction scheme of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide (Example 83) is shown;

[2096] Figure 3 The reaction scheme of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide (Example 85) is shown;

[2097] Figure 4 Shows the reaction scheme of ((2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone (Example 88);

[2098] Figure 5 Shows the reaction scheme of (4-(azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone (Example 89);

[2099] Figure 6 Shows the reaction scheme of (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone (Example 90);

[2100] Figure 7 Shows the reaction scheme of (4,6-dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 92);

[2101] Figure 8 Shows the reaction scheme of (2-ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 93);

[2102] Figure 9 Shows the reaction scheme of (2-(cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 94);

[2103] Figure 10 Shows the reaction scheme of (2-(cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 95);

[2104] Figure 11 Shows the reaction scheme of (2-(cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Example 96);

[2105] Figure 12 Shows the reaction scheme of 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 37);

[2106] Figure 13Shows the reaction scheme of N,N-dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine (Intermediate 42);

[2107] Figure 14 Shows the reaction scheme of N,N-dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine (Intermediate 43);

[2108] Figure 15 Shows the reaction scheme of 1-(isoindolin-5-yl)-N,N-dimethylmethanamine hydrochloride (Intermediate 46); and

[2109] Figure 16 Shows the reaction scheme of 4-((4-methylpiperazin-1-yl)methyl)isoindoline hydrochloride (Intermediate 48). Detailed Description of the Invention

[2110] Abbreviations

[2111] Boc represents tert-butoxycarbonyl

[2112] DAST represents diethylaminosulfur trifluoride

[2113] DBU represents 1,8-diazabicyclo(5.4.0)undec-7-ene

[2114] DCC represents dicyclohexylcarbodiimide

[2115] DCE represents 1,1-dichloroethane

[2116] DCM represents dichloromethane

[2117] DEA represents diethanolamine

[2118] DEAD represents diethyl azodicarboxylate

[2119] DIAD represents diisopropyl azodicarboxylate

[2120] DIBAL represents diisobutylaluminum hydride

[2121] DIPEA represents N,N-diisopropylethylamine, Hünig's base

[2122] DMA represents N,N-dimethylacetamide

[2123] DMAP represents 4-(dimethylamino)pyridine

[2124] DMF represents dimethylformamide

[2125] DMSO represents dimethyl sulfoxide

[2126] EDC represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[2127] EtOAc represents ethyl acetate

[2128] h represents hour

[2129] HATU represents N-[(dimethylamino)-1H-1,2,3-triazol-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide

[2130] HBTU represents (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate

[2131] HOBT represents N-hydroxybenzotriazole

[2132] HPLC represents high performance liquid chromatography

[2133] LAH represents lithium aluminium hydride

[2134] IPA represents isopropyl alcohol

[2135] LCMS represents liquid chromatography - mass spectrometry

[2136] LDA represents lithium diisopropylamide

[2137] LiHMDS represents lithium bis(trimethylsilyl)amide

[2138] mCPBA represents meta-chloroperoxybenzoic acid

[2139] MI represents molecular ion

[2140] Min represents minute

[2141] MgSO4 represents anhydrous magnesium sulfate

[2142] MW represents microwave

[2143] NBS represents N-bromosuccinimide

[2144] NCS represents N-chlorosuccinimide

[2145] NFOBS represents N-fluoro-phthalimide

[2146] NFSI represents N-fluorobenzenesulfonimide

[2147] NHS represents N-hydroxysuccinimide

[2148] NIS represents N-iodosuccinimide

[2149] NMM represents N-methylmorpholine

[2150] NMP represents 1-methyl-2-pyrrolidone

[2151] NMR represents nuclear magnetic resonance

[2152] PdCl2(PPh3)2 represents bis(triphenylphosphine)palladium(II) chloride

[2153] Pd(dppf)2Cl2 represents dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[2154] Pd(dppf)2Cl2.DCM represents the complex of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with DCM

[2155] (Pd(dba)2) represents bis(dibenzylideneacetone)palladium

[2156] Rbf represents round bottom flask

[2157] RT represents retention time

[2158] SCX-2 represents a silica-based adsorbent with chemically bonded propanesulfonic acid functional groups

[2159] SFC represents supercritical fluid chromatography

[2160] TBAF represents tetra-n-butylammonium fluoride

[2161] TBDMS represents tert-butyldimethylsilyl

[2162] TFAA represents trifluoroacetic anhydride

[2163] TFA represents trifluoroacetic acid

[2164] THF represents tetrahydrofuran

[2165] TPP represents tripotassium phosphate

[2166] Ts represents tosyl

[2167] XPhos-Pd-G1 represents (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride

[2168] XPhos-Pd-G2 represents chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[2169] Analytical Methods

[2170] Commercially available starting materials, reagents, and dry solvents were used as received. Flash column chromatography or glass column chromatography was performed using Merck silica gel 230 - 400 mesh. Flash chromatography was also performed on a combi - flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.

[2171] Liquid chromatography - mass spectrometry method

[2172] Method - A

[2173] Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA high - performance mass detector, column: Xbridge BEH C18, 50x2.1 mm, 2.5 μm, column temperature: 35 °C, autosampler temperature: 5 °C, mobile phase A: aqueous solution of 0.1% (v / v) formic acid (pH = 2.70), mobile phase B: water:acetonitrile (10:90) solution of 0.1% formic acid, 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; gradient to t = 3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; run ends at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 minutes. Mass detector parameters: ionization mode cycles through positive and negative modes, cone voltages are 10 V and 30 V, capillary voltage is 0.8 kV, source and probe temperatures are 120 °C and 600 °C respectively.

[2174] Method - B

[2175] The Waters Acquity is equipped with a PDA detector and an SQ detector. Chromatographic column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 μm. Column temperature: 5°C. Mobile phase A: Aqueous solution of 5 mM ammonium bicarbonate (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 ends at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 minutes. Mass detector parameters: Ionization mode cycles through positive and negative modes, cone voltages are 10 V and 30 V, capillary voltage is 3.25 kV, source and probe temperatures are 120°C and 400°C respectively.

[2176] Method - C

[2177] The Waters Acquity UPLC is equipped with a binary solvent manager, a PDA detector and an Acquity QDA high-performance mass detector. Chromatographic column: Ymc Tri-art C18, 50 x 2 mm, 1.9 μm. Column temperature: 35°C. Autosampler temperature: 5°C. Mobile phase A: Aqueous solution of 0.1% (v / v) formic acid (pH = 2.70). Mobile phase B: Aqueous solution of 0.1% formic acid in water:acetonitrile (10:90) solution. 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; gradient to t = 3.51 min (97% A, 3% B), flow rate: 0.8 mL / min; run ends at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 minutes. Mass detector parameters: Ionization mode cycles through positive and negative modes, cone voltages are 10 V and 30 V, capillary voltage is 0.8 kV, source and probe temperatures are 120°C and 600°C respectively.

[2178] Method - D

[2179] Waters Acquity UPLC equipped with a quaternary solvent manager, an SQ detector, and an Acquity QDA mass detector, chromatographic column: X-Bridge BEH C18, 50 * 2.1 mm, 2.5 microns, column temperature: 35 °C, autosampler temperature: 5 °C, mobile phase A: aqueous solution of 0.1% (v / v) formic acid (pH = 2.70), mobile phase B: solution of 0.1% 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; gradient to t = 3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; run ends at t = 4 minutes (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 minutes. Mass detector parameters: ESI capillary probe, ionization mode cycles through positive and negative modes, cone voltage is 10 V and 30 V, capillary voltage is 0.8 kV, source and probe temperatures are 120 °C and 400 °C respectively.

[2180] Method - E

[2181] The Waters Acquity UPLC is equipped with a binary solvent manager, a PDA detector, and an Acquity QDA high-performance mass detector. Chromatographic column: Welch Xtimate C18, 50 x 2.1 mm, 1.8 μm. Column temperature: 35 °C. Autosampler temperature: 5 °C. Mobile phase A: Aqueous solution of 0.1% (v / v) formic acid (pH = 2.70). Mobile phase B: A solution of 0.1% 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; gradient to t = 3.51 min (97% A, 3% B), flow rate: 0.8 mL / min; run ends at t = 4 minutes (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 minutes. Mass detector parameters: Ionization mode cycles through positive and negative modes, cone voltages are 10 V and 30 V, capillary voltage is 0.8 kV, source and probe temperatures are 120 °C and 600 °C respectively.

[2182] NMR

[2183] Unless otherwise stated, the solvents are used at room temperature. 1H nuclear magnetic resonance (NMR) spectroscopic analysis is carried out using a Bruker Avance-400 instrument operating at 400 MHz. The samples are prepared as solutions in appropriate deuterated solvents and referenced to appropriate internal non-deuterated solvent peaks or tetramethylsilane. Chemical shifts are recorded in ppm (δ) relative to tetramethylsilane downfield. In all cases, the NMR data is consistent with the proposed structures. Characteristic chemical shifts (δ) are in parts per million and conventional abbreviations are used to specify the main peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad peak. 1 H nuclear magnetic resonance (NMR) spectroscopic analysis. The samples are prepared as solutions in appropriate deuterated solvents and referenced to appropriate internal non-deuterated solvent peaks or tetramethylsilane. Chemical shifts are recorded in ppm (δ) relative to tetramethylsilane downfield. In all cases, the NMR data is consistent with the proposed structures. Characteristic chemical shifts (δ) are in parts per million and conventional abbreviations are used to specify the main peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad peak.

[2184] Purification Methods

[2185] Preparative purification is carried out by reverse-phase HPLC

[2186] Preparative HPLC Method - A

[2187] Shimadzu Prep-20-AD with a binary pump equipped with a UV / visible wavelength detector, chromatographic column: C18, 250 x 20 mm, 5 μm, column temperature: room temperature, mobile phase A: 0.1% formic acid aqueous solution, 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 ends at t = 21 min (55% A, 45% B), flow rate: 27 mL / min, analysis time 21 min.

[2188] Preparative HPLC Method - B

[2189] Shimadzu Prep-20-AD with a binary pump equipped with an ultraviolet / visible wavelength detector, chromatographic column: C18, 250 x 20 mm, 5 μm, column temperature: room temperature, mobile phase A: 0.1% formic acid aqueous solution, 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 ends at t = 24 min (72% A, 28% B), flow rate: 20 mL / min, analysis time 24 min.

[2190] Preparative HPLC method - C

[2191] Shimadzu LC20AP purification system equipped with a UV detector. Chromatographic column: YMC-Actus Triart prep250*20 mm, 5 μm, room temperature. The compound was eluted with the following: mobile phase A: Milli Q aqueous solution of 0.1% formic acid, mobile phase B: acetonitrile; mobile phase gradient details: t = 0 min (65% A, 35% B); gradient to t = 17 min (35% A, 65% B); t = 17.01 min (2% A, 98% B); gradient to t = 19 min (2% A, 98% B); from t = 19.01 min (65% A, 35% B) to t = 21 min (65% A, 35%); flow rate = 20 mL / min; analysis time 21 min.

[2192] Chiral Preparative HPLC Purification Method

[2193] The enantiomeric separation of the compound was achieved by a chiral preparative HPLC purification method.

[2194] The chiral preparative HPLC purification methods and conditions for resolving enantiomers or determining enantiomeric purity (ee) are listed below.

[2195]

[2196]

[2197] Synthesis

[2198] Several methods for the chemical synthesis of the heterocyclic formamide compounds of the present application are described herein. Within the scope of the present application and the claims, these and / or other well-known methods can be modified and / or adjusted in various ways to facilitate the synthesis of other compounds. Such alternative methods and modifications should be understood to be within the spirit and scope of the present application and the claims. Accordingly, the methods set forth in the following description, schemes, and examples are intended for illustrative purposes and should not be construed as limiting the scope of the present disclosure.

[2199] In one method (Scheme 1), the compound of formula [I] can be prepared by reacting a substituted aromatic carboxylic acid of formula [II] with oxalyl chloride or thionyl chloride in a solvent such as DCM, with an amine of general formula [III] in the presence of a tertiary amine base such as Et3N, DIPEA, or NMM. The reaction is preferably carried out at room temperature. After the reaction workup, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method A). The compound of formula [I] can 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 HBTU or HATU in a polar aprotic solvent such as DMA or DMF, in the presence of a tertiary amine base such as Et3N, DIPEA, or NMM. After the reaction workup, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method B). Then, the ditosyl-protected intermediate (from Method A or B) is subjected to base-induced deprotection with a suitable base such as K2CO3 or KOH in a suitable protic solvent such as MeOH or EtOH. The reaction is preferably carried out at elevated temperature. After the reaction workup, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization to obtain the compound of general formula [I].

[2200] Scheme 1

[2201]

[2202] Example 1: [2,4 - Dihydroxy - 6 - (pyrimidin - 2 - ylmethoxy)phenyl] - pyrrolidin - 1 - yl - methanone

[2203]

[2204] Method 1

[2205] Step - 1: 5-(Pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 40)

[2206] At 0 °C and under a nitrogen atmosphere, HATU (0.29 g, 0.788 mmol, 1.5 eq), DIPEA (0.135 g, 1.051 mmol, 2.0 eq), and pyrrolidine (0.041 g, 0.578 mmol, 1.0 eq) were added to a solution of 2-(pyrimidin-2-ylmethoxy)-4,6-bis(toluenesulfonyloxy)benzoic acid (Intermediate 25) (0.3 g, 0.525 mmol, 1 eq) in DMF (3 mL). The reaction mixture was stirred at 0 °C for 30 min. The resulting reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (eluting the product with a DCM solution of 15% MeOH) to give 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 40) (0.19 g, 58% yield).

[2207] 1 1H NMR (DMSO-d6, 400 MHz): δ 1.73 - 1.75 (m, 4H), 2.42 (s, 3H), 2.45 (s, 3H), 3.40 - 3.50 (m, 4H), 5.26 (d, J = 3.2 Hz, 2H), 6.54 (d, J = 1.6 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 7.43 - 7.53 (m, 5H), 7.65 - 7.41 (m, 4H), 8.80 (d, J = 4.8 Hz, 2H). LCMS (Method A): 2.204 min, MS: ES+ 624.20 (M + 1).

[2208] Step - 2: (2,4-Dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone

[2209] At room temperature, an aqueous solution (0.5 mL) of KOH (1.07 g, 19.24 mmol, 40 equivalents) was added dropwise to a solution of 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 40) (0.6 g, 0.481 mmol, 1 equivalent) in EtOH (0.6 mL). The reaction mixture was heated at 80 °C for 2 hours, cooled, poured into ice-cold water (80 mL), and extracted with ethyl acetate (4 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (eluting the product with a DCM solution of 7% methanol) to give (2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone (0.045 g, 15% yield).

[2210] 1 1H NMR (DMSO-d6, 400 MHz): δ 1.75 - 1.81 (m, 4H), 3.21 - 3.23 (m, 2H), 3.31 - 3.33 (m, 2H), 5.16 (s, 2H), 5.79 (d, J = 1.6 Hz, 1H), 5.92 (d, J = 2.0 Hz, 1H), 7.45 (t, J = 3.5 Hz, 1H), 8.82 (d, J = 4.8 Hz, 2H), 9.36 (s, 1H), 9.41 (s, 1H). LCMS (Method A): 1.033 min, MS: ES+ 316.16 (M + 1).

[2211] Example 2: (2 - (Cyclopentyloxy) - 4,6 - dihydroxyphenyl)(pyrrolidin - 1 - yl)methanone

[2212]

[2213] Method 2

[2214] Step - 1: Synthesis of 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 41)

[2215] At 0 °C and under a nitrogen atmosphere, oxalyl chloride (0.13 g, 1.02 mmol, 1.0 eq) was added dropwise to a solution of 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 20) (0.5 g, 0.91 mmol, 1 eq) in DCM (5 mL). A catalytic amount of DMF (0.5 mL) was added to the reaction mixture at 0 °C, and the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduced pressure to obtain the crude acyl chloride. In another Rbf, a solution of pyrrolidine in THF (0.130 g, 1.83 mmol, 2.0 eq) was treated with TEA (0.18 g, 1.78 mmol, 2.0 eq) at 0 °C. At 0 °C, the crude acyl chloride in DCM (5 mL) was added dropwise to the amine solution. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (2 × 20 ml), dried over Na2SO4 and concentrated in vacuo to give 5-(cyclopentyloxy)-4-(pyrrolidin-1-ylcarbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 41) as a brown oil (0.4 g, 72% yield). The crude material was used in the next step without purification.

[2216] 1 H NMR (DMSO-d6, 400 MHz): 1.37 - 1.44 (m, 2H), 1.53 - 1.55 (m, 4H), 1.65 - 1.80 (m, 6H), 2.43 - 2.45 (m, 6H), 2.50 - 2.51 (m, 1H), 2.83 - 2.94 (m, 1H), 3.24 - 3.40 (m, 2H), 4.60 - 4.70 (m, 1H), 6.57 - 6.60 (m, 2H), 7.48 - 7.54 (m, 4H), 7.73 - 7.77 (m, 4H). LCMS (Method A): 2.509 min, MS: ES+ 600.15 (M+1).

[2217] Step - 2: (2-(Cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone

[2218] At room temperature, KOH (0.74 g, 13.19 mmol, 40 eq) was added to a solution of 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 41) (0.2 g, 0.33 mmol, 1 eq) in MeOH (4 mL). The reaction mixture was heated at 60 °C for 2 h. The resulting reaction mixture was poured into water (30 mL), acidified with saturated KHSO4 solution, and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (eluting the product with a hexane solution of 20% EtOAc) to give (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone (0.030 g, 30.9% yield).

[2219] 1 1H NMR (DMSO-d6, 400 MHz): δ 1.53 - 1.64 (m, 6H), 1.71 - 1.82 (m, 6H), 3.05 (t, J = 6.4 Hz, 2H), 3.32 - 3.34 (m, 2H), 4.64 - 4.66 (m, 1H), 5.86 - 5.91 (m, 2H), 9.30 - 9.34 (m, 2H). LCMS (Method A): 1.434 min, MS: ES+ 292.06 (M + 1).

[2220] According to the above method, the following compounds were prepared using the indicated intermediates

[2221]

[2222]

[2223]

[2224]

[2225]

[2226]

[2227]

[2228]

[2229]

[2230]

[2231]

[2232]

[2233]

[2234]

[2235]

[2236]

[2237]

[2238]

[2239]

[2240]

[2241]

[2242]

[2243]

[2244]

[2245]

[2246]

[2247]

[2248]

[2249]

[2250]

[2251]

[2252]

[2253]

[2254]

[2255]

[2256]

[2257]

[2258]

[2259]

[2260]

[2261]

[2262]

[2263]

[2264]

[2265]

[2266]

[2267]

[2268]

[2269]

[2270]

[2271]

[2272]

[2273]

[2274]

[2275]

[2276]

[2277]

[2278]

[2279]

[2280]

[2281]

[2282]

[2283]

[2284]

[2285]

[2286]

[2287]

[2288]

[2289]

[2290]

[2291]

[2292]

[2293]

[2294]

[2295]

[2296] Example 82: 2 - (2 - (Benzyloxy) - 4,6 - dihydroxy - 3 - methylbenzoyl)isoindoline - 4 - carbonitrile (Reaction Scheme As shown in Figure 1 )

[2297] 4-Bromoisoindoline hydrochloride

[2298] To a stirred solution of tert-butyl 4-bromo-isoindoline-2-carboxylate (0.5 g, 1.67 mmol, 1.0 eq) in DCM (5 mL) at 0 °C was added dropwise 4N HCl dissolved in dioxane (5 mL). The reaction was stirred at room temperature for 2 h. Completion of the reaction was monitored by TLC (9:1; DCM:MeOH). The resulting reaction mixture was concentrated under reduced pressure and the crude product (0.48 g) was triturated with n-pentane (3 × 25 mL) to give the title compound (0.47 g, 2.00 mmol, yield: 100%).

[2299] 1 1H NMR (DMSO-d6, D2O-exchange 400 MHz): δ 4.48 (s, 2H), 4.62 (s, 2H), 7.34 (t, J = 7.6, 15.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 10.06 (s, 2H). LCMS (method A): 0.766 min, MS: ES+ 198.03 (M+1).

[2300] 5-(Benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate)

[2301] Intermediate 22 (0.5 g, 0.86 mmol, 1.0 equiv) was treated with HATU (0.48 g, 1.28 mmol, 1.5 equiv) and DIPEA (0.22 g, 1.71 mmol, 2.0 equiv) in DMF (5 mL) at 0 °C under a nitrogen atmosphere and stirred for 15 minutes. 4-Bromoisoindoline hydrochloride (0.17 g, 0.86 mmol, 1.0 equiv) was added and the resulting reaction mixture was stirred at 0 °C for 1 hour. The reaction completion was monitored by TLC (ethyl acetate∶hexane 1∶1). The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (4 × ...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which has the structural formula (I) as shown below: wherein R 1 and R 3 are both hydroxyl groups; R 2 is hydrogen or fluorine; R 4 selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl and cyclobutyl; R 6 is a (1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, or a group having a structure according to formula (A) shown below: wherein R 7 is hydrogen or methyl; n is 1 or 2; and R 8 is any one of the following structures: where each R 9 is independently selected from the group consisting of fluorine, methyl, and methoxy; R 10 is - NR 11 R 12 , where R 11 and R 12 are connected such that together with the nitrogen atom to which they are attached they form any one of the following ring systems; Any one of the above rings is optionally substituted with 1, 2 or 3 Rs 13 substituted; Each R 13 is independently selected from fluorine, bromine, cyano and the group -L 1 -X 1 -Q 1 Group wherein: L 1 is absent or is a (1-2C) alkylene group; X 1 is absent or is selected from the group consisting of -O-, -C(O)-O-, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, and -NR 14 -, where R 14 is independently selected from the group consisting of hydrogen and (1-2C) alkyl each time it appears; Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1C)alkyl, 4-6 membered heteroaryl and 4-6 membered heteroaryl(1C)alkyl, wherein any of the (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group(1C)alkyl, 4-6 membered heteroaryl or 4-6 membered heteroaryl(1C)alkyl in Q 1 is optionally substituted by one or more groups R 15 ; Each R 15 independently selected from hydroxy, cyano, halogen, (1-3C)alkyl and -C(O)-NR 15a R 15b A group consisting of, wherein R 15a and R 15b are each independently hydrogen or methyl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is hydrogen.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl and cyclobutyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of hydrogen, methyl and ethyl.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of hydrogen and methyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 is (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl, or a group having a structure according to formula (A) shown below: Where n, R 7 and R 8 Each as defined in claim 1.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 is a group having a structure of formula (A) as shown below: Where n, R 7 and R 8 Each as defined in claim 1.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is 1.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 8 has any of the following structures:

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 8 has the following structure:

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 15 is independently selected from the group consisting of a hydroxyl group, a halogen, a (1-3C) alkyl group, and -C(O)-NR 15a R 15b wherein R 15a and R 15b are each independently hydrogen or methyl.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 15 independently selected from the group consisting of hydroxy, (1-3C)alkyl and -C(O)-NR 15a R 15b The group consisting of R 15a and R 15b are each independently hydrogen or methyl.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 15 is independently selected from the group consisting of a hydroxyl group, a halogen, and a (1-3C) alkyl group.

14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following: [2,4-Dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2-(Cyclopentyloxy)-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-isoindolin-2-yl-methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-(1-piperidinyl)methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxypyrrolidin-1-yl]methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxypyrrolidin-1-yl]methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxy-1-piperidinyl]methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidinyl]methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-pyrrolidin-1-yl-methanone; (2-Benzyloxy-3-ethyl-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone; [2,4-Dihydroxy-6-(2-pyridylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2,4-Dihydroxy-6-[(1R)-1-phenoxy]phenyl]-pyrrolidin-1-yl-methanone; [2,4-Dihydroxy-6-[(1R)-1-phenoxy]phenyl]-pyrrolidin-1-yl-methanone; [2-[(4-Fluorophenyl)methoxy]-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone; [2,4-Dihydroxy-6-[(4-methoxyphenyl)methoxy]phenyl]-pyrrolidin-1-yl-methanone; [2,4-Dihydroxy-6-(m-tolylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-(4-methoxyisoindolin-2-yl)methanone; [2,4-Dihydroxy-6-(pyrimidin-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; 2,4-Dihydroxy-6-(1H-pyrazol-3-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2,4-Dihydroxy-6-(1H-1,2,3-triazol-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-(5-bromoisoindolin-2-yl)methanone; Methyl 2-(2-benzyloxy-4,6-dihydroxybenzoyl)isoindoline-5-carboxylate; (2-Benzyloxy-4,6-dihydroxy-phenyl)-(5-methoxyisoindolin-2-yl)methanone; (2-Benzyloxy-4,6-dihydroxy-phenyl)-(5,6-dimethoxyisoindolin-2-yl)methanone; [2,4-Dihydroxy-6-(1-phenoxy)phenyl]-isoindolin-2-yl-methanone; [2,4-Dihydroxy-6-(1-phenoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone; [2,4-Dihydroxy-6-(1-phenoxy)phenyl]-(5,6-dimethoxyisoindolin-2-yl)methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone; 5,7-Dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone; 5,7-Dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]methanone; 5,7-Dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone; [4,6-Dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone; 5,7-Dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone; [2,4-Dihydroxy-6-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(4-bromoisoindolin-2-yl)methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[4-(hydroxymethyl)isoindolin-2-yl]methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[5-[(4-methylpiperazin-1-yl)methyl]isoindolin-2-yl]methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)methanone; (2-Benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,6-naphthyridin-2-yl)methanone; 3,4-Dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone; 3,4-Dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone; [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; 3,4-dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone; (4-aminoisobenzofuran-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisobenzofuran-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone; (3,4-dihydroisoquinolin-2(1H)-yl)(4,6-dihydroxy-3-methyl-2-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(isobenzofuran-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)isobenzofuran-2-yl)methanone; (R)-(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(isoindolin-1-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(isoindolin-1-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-5-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-5-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-4-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide; N-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide; ((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone; (4-(Azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone; 1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile; (4,6-dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; and (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

15. A pharmaceutical composition comprising a compound as defined in any one of claims 1 - 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent.

16. A pharmaceutical composition comprising a compound as defined in any one of claims 1 - 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. Use of a compound as defined in any one of claims 1 - 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 15 or 16 in the manufacture of a medicament for the treatment of: (i) a proliferative disorder in which inhibition of MLH1 and / or PMS2 activity is beneficial; or (ii) a trinucleotide repeat disorder in which inhibition of MLH1 and / or PMS2 activity is beneficial.

18. Use according to claim 17, wherein the proliferative disorder in which inhibition of MLH1 and / or PMS2 activity is beneficial is cancer.

19. The use according to claim 17, wherein the triplet repeat disorder in which inhibiting MLH1 and / or PMS2 activity is beneficial 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 ataxia (SCA).

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