Inhibitors of MLH1 and / or PMS2 for the treatment of cancer

Abstract

The present invention relates to compounds of formula (I) that target the MLH1 and / or PMS2 proteins, which are components of the DNA mismatch repair (MMR) process. [Formula 1] JPEG2023529335000148.jpg61170Formula (I) [wherein, R 1 , R 2 , R 3 , R 4 , R 6 and R 10 and PMS2 are each as defined herein.] The present invention also relates to methods for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders, e.g., cancer, and other diseases or conditions in which MLH1 and / or PMS2 activity is implicated.

Description

[Technical Field]

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

[0002] Cancer is caused by alterations in cell proliferation. More precisely, what makes cells malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intensive research over the past several decades. Such research has identified the most important pathways and associated molecular targets that enable such malignant lesions.

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

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

[0005] Lynch syndrome (LS, formerly named hereditary nonpolyposis colorectal cancer) is the most common cause of hereditary colorectal cancer (CRC), accounting for 2–5% of all cases. LS is also characterized by an increased risk of malignant lesions at several extracolonic sites, including the endometrium, ovaries, stomach, and small intestine, among others. [3] LS has an autosomal dominant inheritance pattern and is caused by germline mutations in the MMR genes MLH1, MSH2, MSH6, or PMS2. Gene expression from one wild-type allele is sufficient for adequate MMR activity until a second hit inactivates the wild-type allele, resulting in MMR deficiency.

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

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

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

[10] .

[0009] It is now accepted that clinical response to immune checkpoint inhibitors requires the presence of tumor neoantigens and the infiltration of T cells that recognize these neoantigens. Higher neoantigen burden is associated with a better response to CTLA-4 and PD-1 blockade in patients with melanoma and non-small cell lung cancer [11, 12, 13]. The number of neoantigens is associated with tumor-specific binding (TMB), and several large-scale studies have confirmed that high TMB correlates with enhanced checkpoint inhibitor response and improved overall survival in several tumor types, including urothelial carcinoma

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

[19] .

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

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

[21] .

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

[0012] Thus, there is strong biological and clinical evidence that emphasizes the need for inhibitors that target the MLH1 and / or PMS2 proteins, the most important components of DNA MMR, to restore anti-tumor immune responses.

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

[0014] Outside of the cancer field, triplet repeat disorders include more than 30 human neurodegenerative and neuromuscular genetic disorders, such as Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar ataxias (SCAs). Such disorders are characterized by the expansion of simple repeats in genomic DNA. These unstable repeats are generally found in different regions of several genes, and their expansions can cause disease through various loss-of-function and gain-of-function pathways, for example, by interfering with the expression or characteristics of gene products or by affecting splicing or antisense regulation. Several mechanisms have been proposed to contribute to repeat instability, including errors during DNA replication, meiotic recombination, transcription, DNA repair, and chromatin remodeling, which can occur at various stages of the cell cycle. There is evidence that a functional MMR pathway is required to maintain the stability of microsatellite sequences: for example, Msh2- / - transgenic mice carrying a copy of human HD exon 1 (containing a CAG repeat) show a reduced expansion of the introduced (CAG)n repeat when compared to their Msh2+ / +HD exon 1 mouse counterparts

[22] .

[0015] Therefore, there is a further need for compounds that target the MLH1 and / or PMS2 components of the DNA MMR process for treating triplet repeat disorders.The present invention was made with the foregoing in mind. (References) 1.Martin-Lopez, JV and R.Fishel, The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome.Fam Cancer, 2013.12(2):p.159-68. 2.Liu, D., G. Keijzers, and L.J. Rasmussen, DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res, 2017.773:p.174-187. 3.Lynch, H.T., et al., Review of the Lynch syndrome:history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.Clin Genet, 2009.76(1):p.1-18. 4.Shlien, A., et al., Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.Nat Genet, 2015.47(3):p.257-62 5.Sehgal, R., et al., Lynch syndrome:an updated review. Genes(Basel), 2014.5(3):p.497-507 6.Willis, J.A., et al., Immune Activation in Mismatch Repair-Deficient Carcinogenesis:More Than Just Mutational Rate.Clin Cancer Res, 2019. 7.Gubin, M.M. and R.D.Schreiber, CANCER. The odds of immunotherapy success. Science, 2015.350(6257):p.158-9. 8.Kloor, M. and M. von Knebel Doeberitz, The Immune Biology of Microsatellite-Unstable Cancer.Trends Cancer, 2016.2(3):p.121-133. 9.Giannakis, M., et al., Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma.Cell Rep, 2016.17(4):p.1206. 10.Lemery, S., P. Keegan, and R. Pazdur, First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication.N Engl J Med, 2017.377(15):p.1409-1412. 11.Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.N Engl J Med, 2015.372(26):p.2509-20. 12.Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science, 2015.348(6230):p.124-8. 13.Van Allen, E.M., et al., Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.Science, 2015.350(6257):p.207-211. 14.Rosenberg, J.E., et al., Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy:a single-arm, multicentre, phase 2 trial.Lancet, 2016.387(10031):p.1909-20. 15.Hellmann, M.D., et al., Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.Cancer Cell, 2018.33(5):p.843-852 e4. 16.Rizvi, H., et al., Molecular Determinants of Response to Anti-Programmed Cell Death(PD)-1 and Anti-Programmed Death-Ligand 1(PD-L1)Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J Clin Oncol, 2018.36(7):p.633-641. 17.Carbone, D.P., et al., First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med, 2017.376(25):p.2415-2426. 18.Hellmann, M.D., et al., Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med, 2018.378(22):p.2093-2104. 19.Hellmann, M.D., et al., Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell, 2018.33(5):p.853-861 e4. 20.Germano, G., et al., Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature, 2017.552(7683):p.116-120. 21.Mandal, R., et al., Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science, 2019.364(6439):p.485-491. 22.Lu, C., et al. DNA sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity.Cancer Cell. 2021, 39(1), 96-108. 23.Guan J., et al., MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1 activates the cGAS-STING pathway.Cancer Cell.2021, 39(1), 109-121, 24.Manley, K., et al., Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice.Nat Genet, 1999.23(4):p.471-3. Summary of the Invention

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

[0017] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

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

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

[0020] According to a further aspect of the present invention there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0021] According to a further aspect of the present invention there is provided a method of treating cancer in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

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

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

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

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

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

[0027] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of a triplet disorder. In particular embodiments, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar degeneration (SCAs).

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

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

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

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

[0032] According to a further aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a triplet disorder. In particular embodiments, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar degeneration (SCAs).

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

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

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

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

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

[0038] In the above aspects of the invention, the proliferative disorder is suitably cancer, and the cancer is suitably a human cancer. In particular, the compounds of the invention are useful in the treatment of any cancer in which mismatch repair inhibition and / or cGAS / STING pathway activation is beneficial. Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, Carney complex, central nervous system tumor, cervical cancer, colorectal cancer, Cowden disease, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor -GIST, germ cell tumors, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia Disease, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis types 1 and 2, nevoid basal cell carcinoma syndrome, oral or oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma , pituitary tumors, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi's or soft tissue), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, vulvar cancer, Waldenström's macroglobulinemia, Werner's syndrome, Wilms' tumor, and xeroderma pigmentosum). Particular cancers of interest include hematological cancers, such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-esophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0039] Features that include optional, suitable, and preferred features with respect to one aspect of the invention may also be features that include optional, suitable, and preferred features with respect to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0040] [Definition] Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0041] "Treating" or "treatment" is understood to include prevention as well as the alleviation of established symptoms of a condition. Thus, "treating" a situation, disorder, or condition or "treatment" of a situation, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the situation, disorder, or condition in a person who may be afflicted with or predisposed to the situation, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the situation, disorder, or condition; (2) inhibiting the situation, disorder, or condition, i.e., (in the case of maintenance treatment) arresting, reducing, or delaying the onset of the disease or its recurrence or at least one of its clinical or subclinical symptoms; or (3) relieving or attenuating the disease, i.e., causing regression of the situation, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0042] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated. For example, in humans or other mammals, it should be understood that a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or the therapeutically effective amount can be the amount required by the guidelines of the U.S. Food and Drug Administration (FDA) or a corresponding foreign regulatory agency for a particular disease and subject to be treated. It should be understood that the determination of appropriate dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical fields.

[0043] "Subject(s)" and "patient(s)," as used herein alone or in combination with one or more other terms, refer to animals (e.g., mammals), particularly humans. Suitably, "subject(s)" and "patient(s)" may be non-human animals (e.g., livestock or household pets) or humans.

[0044] "Pharmaceutically acceptable," as used herein alone or in combination with one or more other terms, generally refers to a material that is chemically and / or physically compatible with other ingredients (e.g., as with respect to a formulation), and / or generally physiologically compatible with its recipient (e.g., a subject, etc.).

[0045] The term "alkyl," as used herein, includes straight-chain and branched-chain alkyl groups. Reference to a particular alkyl group, e.g., "propyl," is specific for the straight-chain version only, and reference to a particular branched-chain alkyl group, e.g., "isopropyl," is specific for the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl.

[0046] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0047] An "alkylene" group is an alkyl group that is positioned between and serves to connect two other chemical groups. "(1-6C) alkylene" means a straight-chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms, such as methylene (-CH-), the ethylene isomers (-CH(CH)- and -CHCH-), the propylene isomers (-CH(CH)CH-, -CH(CHCH)-, -C(CH)-, and -CHCHCH-), pentylene (-CHCHCHCHCHCH-), and the like.

[0048] The term "alkyenyl" refers to straight- and branched-chain alkyl groups containing two or more carbon atoms and at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl, and but-2,3-enyl, including all possible geometric (E / Z) isomers.

[0049] The term "alkynyl" refers to straight- and branched-chain alkyl groups containing two or more carbon atoms and at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0050] "(m-nC)cycloalkyl" means a saturated hydrocarbon ring system containing m to n carbon atoms. Exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicyclo[2.2.1]heptyl.

[0051] The term "alkoxy" refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and t-butoxy.

[0052] The term "haloalkyl," as used herein, refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include -CHF, -CHF, and -CF.

[0053] The term "halo" or "halogeno" refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably fluoro and chloro.

[0054] The terms "carbocyclyl," "carbocyclic," or "carbocycle" mean a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s). Monocyclic carbocyclic rings contain about 3 to 12 (suitably 3 to 7) ring atoms. Bicyclic carbocyclic rings contain 6 to 17 member atoms, suitably 7 to 12 member atoms in the ring. Bicyclic carbocyclic ring(s) can be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, and spiro[3.3]heptanyl.

[0055] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain about 3 to 12 (suitably 3 to 7) ring atoms, with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic ring(s) can be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. In the case of sulfur-containing heterocycles, sulfur-oxide heterocycles containing SO or SO groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide, etc. The heterocycle can contain one or two oxo (=O) or thioxo (=S) substituents.Suitable values ​​for a heterocyclyl group bearing one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As would be understood by one skilled in the art, any heterocycle can be linked to another group by any suitable atom, for example, a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring linked by the ring nitrogen.

[0056] "Bridged ring system" means a ring system in which two rings share two or more atoms, see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0057] By "spiro bicyclic ring systems" we mean that two ring systems share one common spiro carbon atom, i.e., a heterocyclic ring is linked to an additional carbocyclic or heterocyclic ring by a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0058] "Aromatic," as used herein alone or in combination with another term or terms, refers to monocyclic and polycyclic ring systems containing 4n+2 π-electrons, where n is an integer. Aromatic should be understood to refer to and include ring systems containing only carbon atoms (i.e., "aryl") as well as ring systems containing at least one heteroatom selected from N, O, or S (i.e., "heteroaromatic" or "heteroaryl"). Aromatic ring systems may be substituted or unsubstituted.

[0059] "Non-aromatic," as used herein alone or in conjunction with another term or terms, refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated π system. As used herein, non-aromatic refers to and includes ring systems containing only carbon atoms as well as ring systems containing at least one heteroatom selected from N, O, or S. Non-aromatic ring systems may be substituted or unsubstituted.

[0060] The term "heteroaryl" or "aromatic heterocycle" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Heteroaryl includes monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, e.g., 5- and 6-membered fused rings or a bicyclic structure formed from two 6-membered fused rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to three heteroatoms, more usually up to two, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, is less than five.

[0061] Heteroaryl includes, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolyl, and the like. These include linyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other ring(s) is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0062] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0063] Six-membered heteroaryl groups include, for example, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0064] Bicyclic heteroaryl groups include, for example: a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms; and The group may be a group selected from a cyclopentyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms.

[0065] Particular examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0066] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0067] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a particular embodiment, the aryl is phenyl.

[0068] This specification also uses some compound terms to describe groups containing two or more functional groups. Such terms are understood by those skilled in the art. For example, (3-6C)cycloalkyl(m-nC)alkyl includes (m-nC)alkyl substituted with (3-6C)cycloalkyl.

[0069] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and to groups, structures, or molecules that are not substituted. For example, the term "wherein R 1 wherein a / any CH, CH2, CH3 group or heteroatom (i.e., NH) within a group is optionally substituted 1 group is optionally substituted)" is R 1 Suitably, it means that one (any) of the hydrogen radicals of the group is replaced by the associated defined group.

[0070] When optional substituents are selected from "one or more" groups, it is to be understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. In some embodiments, one or more refers to one, two, or three. In other embodiments, one or more refers to one or two. In particular embodiments, one or more refers to one.

[0071] The phrase "compounds of the invention" refers generally and specifically to the compounds disclosed herein.

[0072] When used herein in connection with a measurable value, such as an amount or duration, "about" is meant to encompass a reasonable variation in the value, for example, allowing for experimental error in determining said value.

[0073] [Compound] In one aspect, the present invention provides a compound of structural formula (I) shown below: [ka] [In the formula, R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, and (1-4C)alkoxy, provided that R 1 and R 3 at least one of is hydroxy; R 2 is hydrogen or fluoro; 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 selected from the group consisting of one or more R 5a and the (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups are optionally substituted by one or more R 5b each R 5a are independently selected from halogen or (1-4C)alkoxy; and each R 5b are independently selected from the group consisting of halogen, (1-4C) alkyl, and (1-4C) alkoxy; R 6 is a (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: [ka] (In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is aryl or heteroaryl, said aryl or heteroaryl being selected from one or more R9 each R 9 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (2-3C) alkenyl, or (2-3C) alkynyl; R 10 is -NR 11 R 12 and R 11 and R 12 are linked together with the nitrogen atom to which they are attached so that they form a 5- to 6-membered monocyclic aromatic heterocycle or a 5- to 7-membered monocyclic heterocyclic ring fused to a benzene ring, thereby forming an 8- to 11-membered bicyclic heteroaryl ring; R 10 Any one or more of the rings present in 13 optionally independently substituted with; Each R 13 are halogen, cyano, oxo, epoxy and -L 1 -X 1 -Q 1 base are independently selected from the group consisting of: L 1 is absent or (1-3C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -N(R 14 )-C(O)-NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, (2-4C) alkenyl, and (2-4C) alkynyl; R 14Any (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl in R 14 is), optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy; Q 1 is selected 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, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl; Q 1 Any (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl, or heteroaryl(1-3C)alkyl in Q 1 is), one or more R 15 optionally substituted with a group; Each R 15 is 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)-R15a , -S(O) 0-2 R 15a , -S(O)NR 15a R 15b , and -N(R 15b )-S(O)2R 15a and R 15a and R 15b are each independently hydrogen or (1-3C) alkyl, and R 15a or R 15b Any (1-3C) alkyl moiety present in a R 15a or R 15b is), optionally hydroxy, cyano, halogen, -OR 15c , -NR 15c R 15d and -C(O)-R 15c and R 15c and R 15d are independently selected from hydrogen and (1-2C)alkyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0074] In another aspect, the present invention provides a compound of structural formula (I) shown below: [ka] [In the formula, R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, and (1-4C)alkoxy, provided that R 1 and R 3 at least one of is hydroxy; R 2 is hydrogen or fluoro; 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 selected from the group consisting of one or more R5a and the (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups are optionally substituted by one or more R 5b each R 5a are independently selected from halogen or (1-4C)alkoxy; and each R 5b are independently selected from the group consisting of halogen, (1-4C) alkyl, and (1-4C) alkoxy; R 6 is a (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: [ka] (In the formula, R 7 is hydrogen or (1-3C) alkyl; n is 1 or 2; R 8 is aryl or heteroaryl, said aryl or heteroaryl being selected from one or more R 9 each R 9 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (2-3C) alkenyl, or (2-3C) alkynyl; R 10 is -NR 11 R 12 and R 11 and R 12 are linked together with the nitrogen atom to which they are attached so that they form a 5- to 6-membered monocyclic aromatic heterocycle or a 5- to 7-membered monocyclic heterocyclic ring fused to a benzene ring, thereby forming an 8- to 11-membered bicyclic heteroaryl ring; R 10 Any one or more of the rings present in 13 optionally independently substituted with; Each R13 are halogen, cyano, oxo, epoxy and -L 1 -X 1 -Q 1 base are independently selected from the group consisting of: L 1 is absent or (1-3C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)-, -NR 14 -, -N(R 14 )-C(O)-NR 14 -, -SO2N(R 14 )- or -N(R 14 )SO2-, and R 14 each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, (2-4C) alkenyl, and (2-4C) alkynyl; R 14 wherein any (1-4C) alkyl, (2-4C) alkenyl, or (2-4C) alkynyl is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy; Q 1 is selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (3-8C) cycloalkyl, aryl, heterocyclyl, and heteroaryl; Q 1 Any (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (3-8C) cycloalkyl, aryl, heterocyclyl, or heteroaryl in 15 optionally substituted with a group; Each R 15 is hydroxy, cyano, oxo, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR 15a R 15b , -C(O)-R 15a , -C(O)-OR15a , -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)NR 15a R 15b , and -N(R 15b )-S(O)2R 15a and R 15a and R 15b are each independently hydrogen or (1-3C) alkyl, and R 15a or R 15b Any (1-3C) alkyl moiety present in the group may optionally be selected from hydroxy, cyano, halogen, -OR 15c , -NR 15c R 15d and -C(O)-R 15c and R 15c and R 15d are independently selected from hydrogen and (1-2C)alkyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0075] Particular compounds according to the invention include, for example, compounds of formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, unless otherwise specified, wherein R 1 , R 2 , R 3 , R 4 , R 6 and R 10 (R 11 and R 12 Each of the groups (including ) and any associated substituents has any of the meanings defined above or any of the following paragraphs (1) to (135): (1)R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, halo, and (1-2C)alkoxy, with the proviso that R 1 and R3 At least one of is hydroxy. (2)R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, fluoro, and (1-2C)alkoxy, with the proviso that R 1 and R 3 At least one of is hydroxy. (3)R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, fluoro, and methoxy, with the proviso that R 1 and R 3 At least one of the is hydroxy. (4)R 1 and R 3 are both hydroxyl. (5)R 2 is fluoro. (6)R 2 is hydrogen. (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 selected from the group consisting of one or more R 5a and the (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups are optionally substituted by one or more R 5b is optionally replaced by (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 selected from the group consisting of one, two or three R 5a and the (3-5C)cycloalkyl and (3-5C)cycloalkyl(1-2C)alkyl groups are optionally substituted by one, two or three R 5b is optionally replaced by (9)R 4is 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 selected from the group consisting of one, two or three R 5a and the (3-5C)cycloalkyl and (3-5C)cycloalkyl(1C)alkyl groups are optionally substituted by one, two or three R 5b is optionally replaced by (10)R 4 is selected from the group consisting of hydrogen, halogen, (1-4C) alkyl and (3-5C) cycloalkyl, wherein said (1-4C) alkyl is selected from the group consisting of one or two R 5a and the (3-5C)cycloalkyl group is optionally substituted by one or two R 5b is optionally replaced by (11)R 4 is selected from the group consisting of hydrogen, fluoro, chloro(1-4C)alkyl, cyclopropyl, and cyclobutyl, and said (1-4C)alkyl is selected from the group consisting of one R 5a and the cyclopropyl and cyclobutyl groups are optionally substituted by one R 5b is optionally replaced by (12)R 4 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, ethyl iso-propyl, cyclopropyl and cyclobutyl. (13)R 4 is selected from the group consisting of hydrogen, methyl, ethyl, iso-propyl, cyclopropyl and cyclobutyl. (14)R 4 is selected from the group consisting of hydrogen, methyl and ethyl. (15)R 4 is selected from the group consisting of hydrogen and methyl. (16)R 4 is hydrogen. (17)R 4 is methyl. (18)Each R 5a are independently selected from halogen, hydroxy or (1-3C)alkoxy. (19)Each R 5a are independently selected from fluoro, chloro, hydroxy or (1-2C)alkoxy. (20)Each R 5a is independently selected from fluoro, hydroxy, or methoxy. (21)Each R 5b are independently selected from the group consisting of halogen, hydroxy, (1-3C)alkyl and (1-3C)alkoxy. (22)Each R 5b are independently selected from the group consisting of halogen, hydroxy, (1-2C)alkyl and (1-2C)alkoxy. (23)Each R 5b is independently selected from the group consisting of fluoro, chloro, hydroxy, (1-2C)alkyl and (1-2C)alkoxy. (24)Each R 5b is independently selected from the group consisting of fluoro, chloro, hydroxy, methyl and methoxy. (25)R 7 is hydrogen or (1-2C) alkyl. (26)R 7 is (1-3C) alkyl. (27)R 7 is hydrogen or methyl. (28)R 7 is hydrogen. (29)R 7 is methyl. (30)n is 1. (31)n is 2. (32)R 8 is phenyl or 5- to 6-membered heteroaryl, and said phenyl or 5- to 6-membered heteroaryl is selected from one or more R 9 is optionally replaced by (33)R 8 is phenyl or a 5-6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from N and O, and said phenyl or 5-6 membered heteroaryl is selected from 1, 2 or 3 R 9is optionally replaced by (34)R 8 is phenyl or a 5-6 membered heteroaryl containing 1, 2 or 3 ring N atoms, said phenyl or 5-6 membered heteroaryl being selected from the group consisting of 1, 2 or 3 R 9 is optionally replaced by (35)R 8 has the following structure: [ka] [In the formula, R 9 is as defined herein (or as in any one of paragraphs (44) to (50) below), and each m 1 is independently 0, 1, 2, or 3; each m 2 are independently 0, 1 or 2. (36)R 8 has the following structure: [ka] [In the formula, m 1 is 0, 1, 2 or 3, and R 9 is as defined herein (or as in any one of paragraphs (44) to (50) below). (37)R 8 has the following structure: [ka] [In the formula, R 9 is as defined herein (or as in any one of paragraphs (44) to (50) below). (38)R 8 has the following structure: [ka] It has any one of the following. (39)R 8 has the following structure: [ka] It has. (40) each m 1 are independently 0, 1, or 2; (41) each m 1 are independently 0 or 1; (42) each m 1 is 0. (43) each m 2 are independently 0 or 1; (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. (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. (46)Each R 9 is independently selected from the group consisting of halogen, (1-3C)alkyl, (1-3C)alkoxy, (2C)alkenyl or (2C)alkynyl. (47)Each R 9 are independently selected from the group consisting of halogen, (1-2C) alkyl, (1-2C) alkoxy, (2C) alkenyl, and (2C) alkynyl. (48)Each R 9 is independently selected from the group consisting of fluoro, chloro, (1-3C)alkyl and (1-3C)alkoxy. (49)Each R 9 is independently selected from the group consisting of fluoro, (1-2C)alkyl and (1-2C)alkoxy. (50)Each R 9 is independently selected from the group consisting of fluoro, methyl and methoxy. (51)R 11 and R 12are linked together with the nitrogen atom to which they are attached so that they form a 5- to 6-membered monocyclic aromatic heterocycle or a 5- to 7-membered monocyclic heterocyclic ring fused to a benzene ring, thereby forming an 8- to 11-membered bicyclic heteroaryl ring; any of the rings may be fused to one or more R 13 is optionally replaced by (52)R 11 and R 12 are linked together with the nitrogen atom to which they are attached so that they form a 5- to 6-membered monocyclic aromatic heterocycle or a 5- to 6-membered monocyclic heterocyclic ring fused to a benzene ring, thereby forming an 8- to 10-membered bicyclic heteroaryl ring; any of the rings may be fused to up to two R 13 is optionally replaced by (53)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, v 2 and v 3 are each independently 1 or 2; W 1 is CH, N or O; each A ring is a benzene ring or a 5- to 6-membered aromatic heterocycle; Any ring is composed of one or two R 13 and optionally substituted with . (54)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, v 2 and v 3 are each independently 1 or 2; W 1is CH, N or O; each A ring is a benzene ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N and O; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a 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 halo; each q 2 independently, 0, 1, or 2; each q 3 are independently 0 or 1. (55)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, v 1 is 1, 2 or 3; v 2 and v 3 are each independently 1 or 2; W 1 is CH, N or O; each A ring is a benzene ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 N atoms; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo; each q 2are independently 0, 1, or 2; each q 3 are independently 0 or 1. (56)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1; each q 3 are independently 0, 1, or 2; v 2 and v 3 are each independently 1 or 2; W 2 , W 3 and W 4 are each independently CH, N, or O, provided that W 2 , W 3 and W 4 are N or O; W 5 , W 6 , W 7 and W 8 are each independently CH, N, or O, provided that W 5 , W 6 , W 7 and W 8 are N or O; W 9 is N, O or CH2, W 10 is C or N; W 11 , W 12 and W 13 are each independently CH, N, or O, provided that W 11 , W 12 and W 13 are N or O; W 14 , W15 , W 16 and W 17 are each independently CH, N, or O, provided that W 14 , W 15 , W 16 and W 17 are N or O; W 18 is N, O or CH2, W 19 is C or N; 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 and 0, 1 or 2 of the groups are N or O.]. (57)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1; each q 3 are independently 0, 1, or 2; v 2 and v 3 are each independently 1 or 2; W 2 , W 3 and W 4 are each independently CH or N, provided that W 2 , W 3 and W 4 and 0, 1 or 2 or more of are N; W 5 , W 6 , W 7 and W 8 are each independently CH or N, provided that W5 , W 6 , W 7 and W 8 and 0, 1 or 2 or more of are N; W 9 is N, O or CH2, W 10 is C or N; W 11 , W 12 and W 13 are each independently CH or N, provided that W 11 , W 12 and W 13 and 0, 1 or 2 or more of are N; 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 and 0, 1 or 2 or more of are N; W 18 is N, O or CH2, W 19 is C or N; 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 and 0, 1 or 2 or more of are N; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (58)R 11 and R 12together with the nitrogen atom attached to them, they form the following ring system: [ka] wherein any of the above rings may be substituted with one, two or three R 13 and optionally substituted with . (59)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1, and each q 3 are independently 0, 1, or 2. (60)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1, and each q 3 are independently 0, 1, or 2; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (61)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, v 2 is 1 or 2; Ring A is a benzene ring or a 5- to 6-membered aromatic heterocycle; Either ring may contain one or two R 13 and optionally substituted with . (62)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, v 2 is 1 or 2; Ring A is a benzene ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N and O; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo; each q 2 are independently 0, 1, or 2; each q 3 are independently 0 or 1. (63)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1; each q 3 are independently 0, 1, or 2; v 3 is independently 1 or 2; W 5 , W6 , W 7 and W 8 are each independently CH or N, provided that W 4 , W 5 , W 6 and W 7 and 0, 1 or 2 or more of are N; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (64)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, v 3 is independently 1 or 2; Either ring may contain one or two R 13 and optionally substituted with . (65)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 3 are independently 0 or 1; each q 3 are independently 0, 1, or 2; v 3 are independently 1 or 2. (66)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 3 are independently 0 or 1; each q 3 are independently 0, 1, or 2; v 3 is independently 1 or 2; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (67)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 3 are independently 0 or 1; each q 3 are independently 0, 1 or 2; v 3 are independently 1 or 2. (68)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 3 are independently 0 or 1; each q 3 are independently 0, 1, or 2; v 3 is independently 1 or 2; Each R 13ais independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13a wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (69)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] wherein any of the above rings may be substituted with one, two or three R 13 and optionally substituted with . (70)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1, and each q 3 are independently 0, 1, or 2. (71)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] [In the formula, each q 2 are independently 0 or 1, and each q 3 are independently 0, 1, or 2; Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl, and (1-3C) alkoxy; R 13awherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (72)Each R 13 is halogen, oxo, epoxy and -L (as defined above or in any one of paragraphs (80) to (101) or (126) to (135) below). 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (73)Each R 13 is a halogen, epoxy and -L (as defined above or in any one of paragraphs (97) to (101) or (133) to (135) below). 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (74)Each R 13 is fluoro, bromo, epoxy and -L (as defined above or in any one of paragraphs (99) to (101) or (134) to (135) below); 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (75)Each R 13 is fluoro (as defined above or in any one of paragraphs (100) or (101) or (134) to (135) below) and -L 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (76)Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-2C) alkyl, and (1-2C) alkoxy; R 13a Any (1-2C) alkyl and (1-2C) alkoxy in R 13ais), optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (77)Each R 13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-2C)alkyl, and methoxy; R 13a Any (1-2C) alkyl in R 13a is), optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo. (78)Each R 13a are independently selected from the group consisting of oxo, hydroxy, (1-2C)alkyl, —CH2OH, —CH2F, —CHF2, —CF3, and methoxy. (79)Each R 13a is independently selected from the group consisting of oxo, hydroxy, (1-2C)alkyl, and —CHOH. (80)L 1 is absent or (1-2C) alkylene. (81)L 1 is absent or methylene. (82)L 1 does not exist. (83)L 1 is methylene. (84)X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14 Any (1-4C) alkyl or (2-4C) alkenyl therein is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy. (85)X 1is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14 Any (1-4C) alkyl or (2-4C) alkenyl therein is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy. (86)X 1 is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14 Any (1-4C) alkyl or (2-4C) alkenyl therein is optionally substituted independently with 1, 2 or 3 groups selected from the group consisting of fluoro, chloro and hydroxy. (87)X 1 is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen, cyano, (1-4C) alkyl and (2-4C) alkenyl. (88)X 1 is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen, cyano, and (1-2C)alkyl. (89)X 1 is absent or -O-, -C(O)-O- and -NR 14 -[wherein, R14 is selected from the group consisting of: each occurrence is independently selected from the group consisting of hydrogen and (1-2C)alkyl. (90)Q 1 is selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclyl and heteroaryl; Q 1 Any (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclyl or heteroaryl in 15 Optionally substituted with a group. (91)Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl; Q 1 Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl in 15 Optionally substituted with a group. (92)Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl; Q 1 Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in 15 Optionally substituted with a group. (93)Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, and 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N and O; and Q 1 Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in 15 Optionally substituted with a group. (94)Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl and 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, and Q 1 Any (1-4C) alkyl or 5- or 6-membered heterocyclyl in 15 Optionally substituted with a group. (95)Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl; Q 1 Any (1-2C) alkyl or piperazinyl in 15 Optionally substituted with a group. (96)Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl; Q 1 Any (1-2C) alkyl or piperazinyl in 15 Optionally substituted with a group. (97)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14 wherein any (1-4C) alkyl or (2-4C) alkenyl is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy; Q 1 is selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclyl and heteroaryl; Q 1Any (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclyl or heteroaryl in 15 Optionally substituted with a group. (98)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14 wherein any (1-4C) alkyl or (2-4C) alkenyl is optionally substituted independently with 1, 2, or 3 groups selected from the group consisting of fluoro, chloro, and hydroxy; Q 1 is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl; Q 1 Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in 15 Optionally substituted with a group. (99)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl; Q 1is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, and 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N and O; and Q 1 Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in 15 Optionally substituted with a group. (100)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen, cyano, and (1-2C)alkyl; Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl; Q 1 Any (1-2C) alkyl or piperazinyl in 15 Optionally substituted with a group. (101)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-O- and -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen and (1-2C)alkyl; Q 1 is selected from the group consisting of hydrogen, (1-2C) alkyl and piperazinyl; Q 1 Any (1-2C) alkyl or piperazinyl in 15 Optionally substituted with a group. (102)Each R 15is 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 and -N(R 15b )C(O)-R 15a and R 15a and R 15b are each independently hydrogen or (1-3C) alkyl, and R 15a or R 15b Any (1-3C) alkyl moiety present in the group may be hydroxy, cyano, halogen, -NR 15c R 15d , -C(O)-NR 15c R 15d and -N(R 15c )C(O)-R 15d and R 15c and R 15d are independently selected from hydrogen and (1-2C)alkyl. (103) Each R 15 is 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 and R 15a and R 15b are each independently hydrogen or (1-3C) alkyl, and R 15a or R 15b Any (1-3C) alkyl moiety present in the group may be substituted with hydroxy, halogen, and -NR 15c R 15d and R 15c and R 15dare independently selected from hydrogen and (1-2C)alkyl. (104) Each R 15 is hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR 15a R 15b and -C(O)-NR 15a R 15b and R 15a and R 15b are each independently hydrogen or (1-3C) alkyl. (105) Each R 15 is hydroxy, cyano, halogen, (1-3C) alkyl and -C(O)-NR 15a R 15b and R 15a and R 15b are each independently hydrogen or methyl. (106) Each R 15 is hydroxy, halogen, (1-3C) alkyl and -C(O)-NR 15a R 15b and R 15a and R 15b are each independently hydrogen or methyl. (107) Each R 15 is hydroxy, (1-3C) alkyl and -C(O)-NR 15a R 15b and R 15a and R 15b are each independently hydrogen or methyl. (108) Each R 15 is independently selected from the group consisting of hydroxy, halogen and (1-3C)alkyl. (109)R 6 is a (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (110)R 6 is a (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (111)R 6 is a 5- or 6-membered heterocyclyl ring containing one heteroatom selected from (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or O or S, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (112)R 6 is a (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or tetrahydropyran, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (113)R 6 is a (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (114)R 6 is a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (115)R 6 is a (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (116)R 6 is a (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (117)R 6 is a 5- or 6-membered heterocyclyl ring containing one heteroatom selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or O or S, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (118)R 6 is a (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: [ka] [where n, R 7 and R 8 are each as defined herein. (119)R 6 is a (1-2C) alkyl, (3-6C) cycloalkyl or (3-6C) cycloalkyl(1-2C) alkyl, or a group having a structure according to formula (A) shown below: [ka] [where n, R 7 and R 8 are each as defined herein. (120)R 6 is methyl. (121)R 6 is ethyl. (122)R 11 and R 12 together with the nitrogen atom attached to them, they form the following ring system: [ka] wherein any of the above rings may be substituted with one, two or three R 13 and optionally substituted with . (123) Each R 13is selected from halogen, cyano, oxo, epoxy and -L (as defined anywhere herein). 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (124)Each R 13 is halogen, cyano, epoxy and -L (as defined anywhere herein or in any one of paragraphs (97) to (101) or (133) to (135)). 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (125) Each R 13 is fluoro, bromo, cyano, epoxy, and -L (as defined anywhere herein or in any one of paragraphs (99) to (101) or (133) to (135)). 1 -X 1 -Q 1 are independently selected from the group consisting of groups. (126)X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14 Any (1-4C) alkyl or (2-4C) alkenyl therein is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy. (127)X 1 is absent or -O-, -C(O)-, -C(O)-O-, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, and R 14is independently selected at each occurrence from the group consisting of hydrogen, cyano, and (1-2C)alkyl. (128)X 1 is absent or -O-, -C(O)-O-, -C(O)-N(R 14 )- and -N(R 14 )-C(O)-, -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen and (1-2C)alkyl. (129)Q 1 is selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl; Q 1 Any (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl, or heteroaryl(1-3C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group. (130)Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl and heteroaryl(1-2C)alkyl; Q 1 Any (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group. (131)Q 1is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1-2C)alkyl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl(1-2C)alkyl, 4- to 6-membered heteroaryl and 4- to 6-membered heteroaryl(1-2C)alkyl; Q 1 Any of the (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1-2C)alkyl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl(1-2C)alkyl, 4- to 6-membered heteroaryl, or 4- to 6-membered heteroaryl(1-2C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group. (132)Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl(1C)alkyl, 4- to 6-membered heteroaryl, and 4- to 6-membered heteroaryl(1C)alkyl; Q 1 Any of the (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl(1C)alkyl, 4- to 6-membered heteroaryl, or 4- to 6-membered heteroaryl(1C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group. (133)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0~2 -, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R 14wherein any (1-4C) alkyl or (2-4C) alkenyl is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy; Q 1 is selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl; Q 1 Any (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl, or heteroaryl(1-3C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group. (134)L 1 is absent or (1-2C) alkylene; X 1 is absent or -O-, -C(O)-, -C(O)-O-, -C(O)-N(R 14 )-, -N(R 14 )-C(O)- or -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen, cyano, and (1-2C)alkyl; Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl and heteroaryl(1-2C)alkyl; Q 1 Any (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group. (135)L 1 is absent or (1-2C) alkylene; X1 is absent or -O-, -C(O)-O-, -C(O)-N(R 14 )- and -N(R 14 )-C(O)-, -NR 14 -, and R 14 is independently selected at each occurrence from the group consisting of hydrogen and (1-2C)alkyl; Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl(1C)alkyl, 4- to 6-membered heteroaryl, and 4- to 6-membered heteroaryl(1C)alkyl; Q 1 Any of the (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl(1C)alkyl, 4- to 6-membered heteroaryl, or 4- to 6-membered heteroaryl(1C)alkyl may be selected from the group consisting of one or more R 15 Optionally substituted with a group.

[0076] Appropriately, R 1 and R 3 is as defined in numbered paragraph (3) or (4). Most appropriately, R 1 and R 3 is as defined in numbered paragraph (4).

[0077] Appropriately, R 2 is as defined in numbered paragraph (6).

[0078] Appropriately, R 4 is as defined in any one of the numbered paragraphs (10) to (17). More appropriately, R 4 is as defined in any one of the numbered paragraphs (13) to (17). Most appropriately, R 4 is as defined in any one of the numbered paragraphs (15) to (17).

[0079] Appropriately, R 5a is as defined in the numbered paragraph (19) or (20). Most appropriately, R 5a is as defined in numbered paragraph (20).

[0080] Appropriately, R 5b is as defined in the numbered paragraph (23) or (24). Most appropriately, R 5a is as defined in numbered paragraph (24).

[0081] Appropriately, R 7 is as defined in any one of the numbered paragraphs (27) to (29). Most appropriately, R 7 is as defined in numbered paragraph (28).

[0082] Suitably, n is as defined in numbered paragraph (30).

[0083] Appropriately, R 8 is as defined in any one of the numbered paragraphs (34) to (39). More appropriately, R 8 is as defined in any one of the numbered paragraphs (36) to (39). Most appropriately, R 8 is as defined in numbered paragraph (39).

[0084] Appropriately, m 1 is as defined in the numbered paragraph (41) or (42). Most suitably, m 1 is as defined in numbered paragraph (42).

[0085] Appropriately, R 9 is as defined in any one of the numbered paragraphs (46) to (50). More appropriately, R 9is as defined in any one of the numbered paragraphs (48) to (50). Most appropriately, R 9 is as defined in numbered paragraph (50).

[0086] Appropriately, R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71). More appropriately, R 11 and R 12 is as defined in any one of the numbered paragraphs (57) to (71). Even more appropriately, R 11 and R 12 is as defined in any one of the numbered paragraphs (61) to (71). Even more appropriately, R 11 and R 12 is as defined in any one of the numbered paragraphs (64) to (71). Even more appropriately, R 11 and R 12 is as defined in any one of the numbered paragraphs (67) to (71). Most appropriately, R 11 and R 12 is as defined in the numbered paragraph (70) or (71).

[0087] Appropriately, R 11 and R 12 is as defined in numbered paragraph (122).

[0088] Appropriately, R 13 is as defined in the numbered paragraph (74) or (75).

[0089] Appropriately, R 13a is as defined in the numbered paragraph (78) or (79).

[0090] Appropriately, L 1is as defined in any one of the numbered paragraphs (81) to (83).

[0091] Appropriately, X 1 is as defined in any one of the numbered paragraphs (86) to (89). More appropriately, X 1 is as defined in the numbered paragraph (88) or (89).

[0092] Appropriately, X 1 is as defined in any one of the numbered paragraphs (126) to (128). More appropriately, X 1 is as defined in numbered paragraph (128).

[0093] Appropriately, Q 1 is as defined in any one of the numbered paragraphs (93) to (96). More appropriately, Q 1 is as defined in any one of the numbered paragraphs (95) or (96).

[0094] Appropriately, Q 1 is as defined in any one of the numbered paragraphs (129) to (132). More appropriately, Q 1 is as defined in any one of the numbered paragraphs (130) or (132). Most appropriately, Q 1 is as defined in the numbered paragraph (131) or (132).

[0095] Appropriately, L 1 , X 1 and Q 1 is as defined in any one of the numbered paragraphs (99) to (101).

[0096] Appropriately, L 1 , X 1 and Q 1is as defined in any one of the numbered paragraphs (133) to (135). Most appropriately, L 1 , X 1 and Q 1 is as defined in the numbered paragraph (134) or (135).

[0097] Appropriately, R 15 is as defined in any one of the numbered paragraphs (105) to (108). More appropriately, R 15 is as defined in the numbered paragraph (107) or (108).

[0098] Appropriately, R 6 is as defined in any one of the numbered paragraphs (109) to (114). More appropriately, R 6 is as defined in any one of the numbered paragraphs (111), (112), (113) or (114).

[0099] Appropriately, R 6 is as defined in any one of the numbered paragraphs (115) to (121). More appropriately, R 6 is as defined in any one of the numbered paragraphs (118), (119), (120) or (121).

[0100] In one particular group of compounds according to the invention, the compounds have formula II (which is a sub-definition of formula I): [ka] [where n, R 2 , R 4 , R 7 , R 8 , R 10and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0101] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (31) to (39); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); All other groups are as defined in any of the numbered paragraphs above.

[0102] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8is as defined in any one of the numbered paragraphs (34) to (39); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0103] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R11 and R 12 is as defined in any one of the numbered paragraphs (57) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0104] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12is as defined in any one of the numbered paragraphs (61) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0105] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R12 is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0106] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0107] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0108] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1, X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0109] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in numbered paragraph (70) or (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0110] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in numbered paragraph (70); R 13 is as defined in numbered paragraph (74); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (99); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0111] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in any one of numbered paragraphs (67) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (123) to (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0112] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12is as defined in any one of numbered paragraphs (70) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (124) to (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (134) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0113] In one embodiment of the compound of Formula II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in numbered paragraph (122); R 13 is as defined in the numbered paragraph (74) or (124); R 13a is as defined in numbered paragraph (78); L 1 , X 1and Q 1 is as defined in numbered paragraph (134) or (135); R 15 is as defined in numbered paragraph (107);

[0114] All other groups are as defined in any of the numbered paragraphs above. In one particular group of compounds according to the invention, the compound has formula I-II (which is a subdefinition of formula I): [ka] [where n, m 1 , R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , R 10 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0115] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); All other groups are as defined in any of the numbered paragraphs above.

[0116] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0117] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (57) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0118] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (61) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); R 15is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0119] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0120] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0121] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0122] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0123] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in numbered paragraph (70) or (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0124] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3); m 1 is as defined in numbered paragraph (41); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 9 is as defined in numbered paragraph (48); R 11 and R 12 is as defined in numbered paragraph (70); R 13 is as defined in numbered paragraph (74); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (99); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0125] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (67) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (123) to (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0126] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (70) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (124) to (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (134) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0127] In one embodiment of the compound of Formula I-II, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3); m 1 is as defined in numbered paragraph (41); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 9 is as defined in numbered paragraph (48); R 11 and R 12 is as defined in numbered paragraph (122); R 13 is as defined in the numbered paragraph (74) or (123); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (134) or (135); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0128] In one particular group of compounds according to the invention, the compounds have formula I-III (which are subdefinitions of formula I): [ka] [where n, m 1 , R2 , R 4 , R 7 , R 9 , R 10 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0129] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); All other groups are as defined in any of the numbered paragraphs above.

[0130] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0131] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (57) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0132] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R12 is as defined in any one of the numbered paragraphs (61) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0133] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R12 is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0134] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0135] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0136] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0137] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in numbered paragraph (70) or (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0138] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 9 is as defined in numbered paragraph (48); R 11 and R 12 is as defined in numbered paragraph (70); R 13 is as defined in numbered paragraph (74); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (99); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0139] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (67) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (123) to (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0140] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (70) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (124) to (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (134) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0141] In one embodiment of the compound of Formula I-III, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41); R 2is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 9 is as defined in numbered paragraph (48); R 11 and R 12 is as defined in numbered paragraph (122); R 13 is as defined in the numbered paragraph (74) or (123); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (134) or (135); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0142] In one particular group of compounds according to the invention, the compounds have formula I-IV (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (53); n, R 2 , R 4 , R 7 and R 8and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0143] In one particular group of compounds according to the invention, the compounds have formula IV (which is a subdefinition of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (56); n, R 2 , R 4 , R 7 and R 8 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0144] In one particular group of compounds according to the invention, the compounds have the formula I-VI (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (65) or (66); n, R 2 , R 4 , R 7 and R 8 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0145] In one particular group of compounds according to the invention, the compounds have formula I-VII (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (68); n, R 2 , R 4 , R 7 and R 8 and any related subgroups are as defined in any of the numbered paragraphs above], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0146] In one particular group of compounds according to the invention, the compounds have formula I-VIII (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (70) or (71); n, R 2 , R 4 , R 7 and R 8 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0147] In one particular group of compounds according to the invention, the compounds have the formula I-VIIIa (which is a subdefinition of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (122); n, R 2 , R 4 , R 7 and R 8 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0148] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (31) to (39); All other groups are as defined in any of the numbered paragraphs above.

[0149] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (34) to (39); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0150] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0151] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0152] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0153] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0154] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0155] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13 is as defined in numbered paragraph (74) or (75); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0156] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13is as defined in numbered paragraph (74) or (75); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0157] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13 is as defined in numbered paragraph (74); L 1 , X 1 and Q 1 is as defined in numbered paragraph (100); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0158] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII or I-VIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (17); R 7 is as defined in numbered paragraph (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13 is as defined in numbered paragraph (75); L 1 , X 1 and Q 1 is as defined in numbered paragraph (101); R 15 is as defined in numbered paragraph (108); All other groups are as defined in any of the numbered paragraphs above.

[0159] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII, I-VIII or I-VIIIa, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13 is as defined in any one of numbered paragraphs (74), (75) or (123) to (125); L1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0160] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII, I-VIII or I-VIIIa, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13 is as defined in the numbered paragraph (74) or (123); L 1 , X 1 and Q 1 is as defined in numbered paragraph (100) or (134); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0161] In one embodiment of the compound of Formula I-IV, IV, I-VI, I-VII, I-VIII or I-VIIIa, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (17); R 7 is as defined in numbered paragraph (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 13 is as defined in numbered paragraph (75) or (125); L 1 , X 1 and Q 1 is as defined in numbered paragraph (134) or (135); R 15 is as defined in numbered paragraph (108); All other groups are as defined in any of the numbered paragraphs above.

[0162] In one particular group of compounds according to the invention, the compounds have formula I-IX (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (56); n, m 1 , R 1 , R 2 , R 3 , R 4 , R 7 and R 9 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0163] In one particular group of compounds according to the invention, the compound has formula IX (which is a subdefinition of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (68); n, m 1 , R 1 , R 2 , R 3 , R 4 , R 7 and R 9 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0164] In one particular group of compounds according to the invention, the compounds have the formula I-Xa (which is a subdefinition of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (122); n, m 1 , R 1 , R 2 , R 3 , R 4 , R 7 and R 9 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0165] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); All other groups are as defined in any of the numbered paragraphs above.

[0166] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R9 is as defined in any one of numbered paragraphs (46) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0167] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0168] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1is as defined in any one of the numbered paragraphs (93) to (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0169] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0170] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0171] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0172] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (74) or (75); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0173] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (74) or (75); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0174] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in paragraph (3); m 1 is as defined in numbered paragraph (41); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (74); L 1 , X 1 and Q 1 is as defined in numbered paragraph (100); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0175] In one embodiment of the compound of Formula I-IX or IX, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in paragraph (4); m 1 is as defined in numbered paragraph (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (17); R 7 is as defined in numbered paragraph (29); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (75); L 1 , X 1 and Q 1 is as defined in numbered paragraph (101); R 15 is as defined in numbered paragraph (108); All other groups are as defined in any of the numbered paragraphs above.

[0176] In one embodiment of the compound of Formula I-IX, IX or I-Xa, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in numbered paragraph (3) or (4); m 1 is as defined in numbered paragraph (41) or (42); R 2is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 13 is as defined in any one of numbered paragraphs (74), (75) or (123) to (125); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in either numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0177] In one embodiment of the compound of Formula I-IX, IX or I-Xa, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in paragraph (3); m 1 is as defined in numbered paragraph (41); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 13is as defined in the numbered paragraph (74) or (123); L 1 , X 1 and Q 1 is as defined in numbered paragraph (100) or (134); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0178] In one embodiment of the compound of Formula I-IX, IX or I-Xa, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 1 and R 3 is as defined in paragraph (4); m 1 is as defined in numbered paragraph (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (17); R 7 is as defined in numbered paragraph (29); n is as defined in numbered paragraph (30); R 13 is as defined in the numbered paragraph (75) or (124); L 1 , X 1 and Q 1 is as defined in numbered paragraph (134) or (135); R 15 is as defined in numbered paragraph (108); All other groups are as defined in any of the numbered paragraphs above.

[0179] In one particular group of compounds according to the invention, the compounds have the formulae I-XI (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (56); n, m 1 , R 2 , R 4 , R 7 and R 9 and any related subgroups are as defined in any of the numbered paragraphs above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0180] In one particular group of compounds according to the invention, the compounds have the formula I-XII (which are subdefinitions of formula I): [ka] [In the formula, R 10 is -NR 11 R 12 and R 11 and R 12 is as defined in numbered paragraph (68); n, m 1 , R 2 , R 4 , R 7 and R 9 and any related subgroups are as defined in any of the numbered paragraphs above], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0181] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); All other groups are as defined in any of the numbered paragraphs above.

[0182] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0183] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0184] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0185] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0186] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0187] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0188] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 13is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0189] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41) or (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0190] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (41); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (74); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (100); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0191] In one embodiment of the compound of Formula I-XI or I-XII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, m 1 is as defined in numbered paragraph (42); R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (17); R 7is as defined in numbered paragraph (29); n is as defined in numbered paragraph (30); R 13 is as defined in numbered paragraph (75); R 13a is as defined in numbered paragraph (79); L 1 , X 1 and Q 1 is as defined in numbered paragraph (101); R 15 is as defined in numbered paragraph (108); All other groups are as defined in any of the numbered paragraphs above.

[0192] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (109), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0193] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (110), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0194] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (111), and R 1 , R 2 , R 3 , R4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0195] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (112), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0196] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (113), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0197] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (114), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0198] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (115), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8and R 10 is as defined in any of the numbered paragraphs above.

[0199] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (116), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0200] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (117), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0201] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (118), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0202] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (119), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10is as defined in any of the numbered paragraphs above.

[0203] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (120), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0204] In certain groups of compounds of formula I, R 6 is as defined above in paragraph (121), and R 1 , R 2 , R 3 , R 4 ,n,R 7 , R 8 and R 10 is as defined in any of the numbered paragraphs above.

[0205] In one particular group of compounds according to the invention, the compounds have the formula I-XIII (which is a subdefinition of formula I): [ka] [In the formula, R 2 , R 4 , and R 10 and any associated subgroups are as defined in any of the numbered paragraphs above; 6 is as defined in any one of paragraphs (109) to (121) above.], or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

[0206] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (109).

[0207] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (110).

[0208] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (111).

[0209] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (112).

[0210] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (113).

[0211] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (114).

[0212] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (115).

[0213] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (116).

[0214] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R6 is as defined above in paragraph (117).

[0215] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (118).

[0216] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (119).

[0217] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (120).

[0218] In one embodiment of the compound of Formulas I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 6 is as defined above in paragraph (121).

[0219] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 6 is as defined in any one of the numbered paragraphs (109) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8is as defined in any one of the numbered paragraphs (31) to (39); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); All other groups are as defined in any of the numbered paragraphs above.

[0220] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 6 is as defined in any one of the numbered paragraphs (111) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (34) to (39); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (53) to (71); R 13 is as defined in numbered paragraph (74) or (75); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0221] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (57) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); All other groups are as defined in any of the numbered paragraphs above.

[0222] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (61) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (93); X 1 is as defined in any one of the numbered paragraphs (86) to (89); Q 1 is as defined in any one of the numbered paragraphs (93) to (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0223] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (64) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13ais as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0224] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of the numbered paragraphs (64) to (71); R 13is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in numbered paragraph (88) or (89); Q 1 is as defined in numbered paragraph (95) or (96); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0225] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0226] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in numbered paragraph (113) or (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in any one of the numbered paragraphs (67) to (71); R 13 is as defined in numbered paragraph (74) or (75); R13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0227] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in numbered paragraph (113) or (114); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in numbered paragraph (70) or (71); R 13 is as defined in numbered paragraph (74) or (75); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1is as defined in any one of numbered paragraphs (99) to (101); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0228] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 6 is as defined in numbered paragraph (113); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in numbered paragraph (70); R 13 is as defined in numbered paragraph (74); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (99); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0229] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of numbered paragraphs (10) to (17); R 6 is as defined in any one of the numbered paragraphs (109) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (31) to (39); R 11 and R 12 is as defined in any one of numbered paragraphs (53) to (71) or (122); All other groups are as defined in any of the numbered paragraphs above.

[0230] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 6 is as defined in any one of numbered paragraphs (111) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R8 is as defined in any one of the numbered paragraphs (34) to (39); R 9 is as defined in any one of numbered paragraphs (46) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (53) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (123) to (125); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of numbered paragraphs (86) to (89) or (126) to (128); Q 1 is as defined in any one of numbered paragraphs (93) to (96) or (129) to (132); All other groups are as defined in any of the numbered paragraphs above.

[0231] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (57) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75), (124) or (125); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of numbered paragraphs (86) to (89) or (126) to (128); Q 1 is as defined in any one of numbered paragraphs (93) to (96) or (130) to (132); All other groups are as defined in any of the numbered paragraphs above.

[0232] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4 is as defined in any one of the numbered paragraphs (13) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (121); R 7is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (61) to (71) or (122); R 13 is as defined in any one of the numbered paragraphs (74), (75) or (123); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of numbered paragraphs (86) to (89) or (126) to (128); Q 1 is as defined in any one of numbered paragraphs (93) to (96) or (131) to (132); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0233] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (5) or (6); R 4is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114) or (119) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (64) to (71) or (122); R 13 is as defined in numbered paragraph (74), (75) or (123); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of numbered paragraphs (88) to (89) or (127) to (128); Q 1 is as defined in any one of numbered paragraphs (95) to (96) or (131) to (132); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0234] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114) or (119) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (64) to (71) or (122); R 13 is as defined in numbered paragraph (74), (75) or (123); R 13a is as defined in numbered paragraph (78) or (79); L 1 is as defined in any one of the numbered paragraphs (81) to (83); X 1 is as defined in any one of numbered paragraphs (88) to (89) or (127) to (128); Q 1 is as defined in any one of numbered paragraphs (95) to (96) or (131) to (132); R 15is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0235] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (112) to (114) or (119) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in any one of the numbered paragraphs (36) to (39); R 9 is as defined in any one of numbered paragraphs (48) to (50); R 11 and R 12 is as defined in any one of numbered paragraphs (67) to (71) or (122); R 13 is as defined in any one of numbered paragraphs (74), (75) or (124); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in any one of numbered paragraphs (105) to (108); All other groups are as defined in any of the numbered paragraphs above.

[0236] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (113) to (114) or (120) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in any one of numbered paragraphs (67) to (71) or (122); R 13 is as defined in the numbered paragraph (74), (75) or (124); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0237] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in any one of numbered paragraphs (15) to (17); R 6 is as defined in any one of numbered paragraphs (113) to (114) or (120) to (121); R 7 is as defined in any one of the numbered paragraphs (27) to (29); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in any one of numbered paragraphs (70) to (71) or (122); R 13 is as defined in the numbered paragraph (74), (75) or (124); R 13a is as defined in numbered paragraph (78) or (79); L 1 , X 1 and Q 1 is as defined in any one of numbered paragraphs (99) to (101) or (133) to (135); R 15 is as defined in numbered paragraph (107) or (108); All other groups are as defined in any of the numbered paragraphs above.

[0238] In one embodiment of the compound of Formula I-XIII, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 is as defined in numbered paragraph (6); R 4 is as defined in numbered paragraph (15); R 6 is as defined in numbered paragraph (113); R 7 is as defined in numbered paragraph (27); n is as defined in numbered paragraph (30); R 8 is as defined in numbered paragraph (39); R 11 and R 12 is as defined in numbered paragraph (122); R 13 is as defined in the numbered paragraph (74) or (125); R 13a is as defined in numbered paragraph (78); L 1 , X 1 and Q 1 is as defined in numbered paragraph (134) or (135); R 15 is as defined in numbered paragraph (107); All other groups are as defined in any of the numbered paragraphs above.

[0239] Particular compounds according to the invention include any of the compounds exemplified in this application, or a pharmaceutically acceptable salt or solvate thereof, in particular any of the following: [2,4-Dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2-(cyclopentoxy)-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-piperidyl)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-piperidyl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidyl]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-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-[(1R)-1-phenylethoxy]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-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-dihydroxy-benzoyl)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-phenylethoxy)phenyl]-isoindolin-2-yl-methanone; [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone; [2,4-dihydroxy-6-(1-phenylethoxy)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; 3,4-Dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisoindolin-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)(isoindolin-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)isoindolin-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)(indolin-1-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(indolin-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-dimethylisoindoline-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-dimethylisoindoline-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.

[0240] The various functional groups and substituents that make up the compounds of formula (I) or sub-formulae (II) to (I-XII) are typically chosen so that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, the molecular weight of the compound is less than 900, e.g., less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, e.g., less than 550.

[0241] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid-addition salts of the compounds of the present invention, for example, acid-addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methane sulfonate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that form pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0242] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates plane-polarized light and can be named dextrorotatory or levorotatory (i.e., (+)- or (-)-isomer, respectively). Chiral compounds can exist as either enantiomer or a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0243] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include both individual enantiomers and their mixtures, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E- and Z-isomers).

[0244] It is to be understood that the present invention embraces all optical, diastereomeric, and geometric isomers and mixtures thereof that possess activity.

[0245] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions, e.g., H can be in any isotopic form, including 1H, 2H (D), and 3H (T); C can be in any isotopic form, including 12C, 13C, and 14C; O can be in any isotopic form, including 16O and 18O, etc.

[0246] It is also to be understood that some compounds of formula (I), or subformulas (II) through (I-XII), can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, etc. It is to be understood that the present invention encompasses all such solvated forms that possess activity.

[0247] It is also to be understood that some compounds of formula (I), or subformulas (II) to (I-XII), may exhibit polymorphism, and that the present invention encompasses all such forms that possess activity.

[0248] Compounds of formula (I), or subformulas (II) to (I-XII), can exist in many different tautomeric forms, and references to compounds of formula (I), or subformulas (II) to (I-XII), include all such forms. For the avoidance of doubt, compounds may exist in one of several tautomeric forms, and only one will be described or shown in detail, while all others are encompassed by formula (I), or subformulas (II) to (I-XII). Examples of tautomeric forms include, for example, the keto, enol, and enolate forms for the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0249] [ka]

[0250] Compounds of formula (I) or sub-formulas (II) to (I-XII) containing an amine functional group can also form N-oxides. References herein to compounds of formula (I) or sub-formulas (II) to (I-XII) containing an amine functional group also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, the N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compounds are reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0251] The compounds of formula (I), or subformulas (II) to (I-XII), can be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the invention. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain a suitable group or substituent to which a property-modifying group can be attached. Prodrugs include, for example, in vivo cleavable ester derivatives that can be formed at carboxy or hydroxy groups in compounds of formula (I), or subformulas (II) to (I-XII), and in vivo cleavable amide derivatives that can be formed at carboxy or amino groups in compounds of formula (I), or subformulas (II) to (I-XII).

[0252] Thus, the present invention includes compounds of formula (I), or sub-formulas (II) to (I-XII), as defined above, when available by organic synthesis and when available in the human or animal body as cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula (I), or sub-formulas (II) to (I-XII), produced by organic synthetic means, and also compounds produced in the human or animal body as metabolism of precursor compounds that are compounds of formula (I), or sub-formulas (II) to (I-XII), which may be synthetically produced compounds or metabolically produced compounds.

[0253] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or subformulas (II) to (I-XII), are those based on sound medical judgment, such that they are free from undesirable pharmacological activity and are free from undue toxicity and are suitable for administration to the human or animal body.

[0254] Various forms of prodrugs are described, for example, in the following documents: a)Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder, et al.(Academic Press, 1985); b)Design of Pro-drugs, edited by H.Bundgaard,(Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); f) N.Kakeya, et al., Chem.Pharm.Bull., 32, 692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0255] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or sub-formulas (II) to (I-XII), which have a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I, or sub-formulas (II) to (I-XII), which contain a carboxy group are, for example, pharmaceutically acceptable esters which are cleaved in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl ester, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthalidyl ester, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester.

[0256] Suitable pharmaceutically acceptable prodrugs of the compounds of Formula (I) or sub-formulas (II) to (I-XII) having a hydroxy group include, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of the compounds of Formula (I) or sub-formulas (II) to (I-XII) containing a hydroxy group include, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters, such as phosphate esters (including phosphoramidate cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include (1-10C)alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and (1-10C)alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(1-6C)2carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(1-4C)alkylpiperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for hydroxy groups include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl groups.

[0257] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or sub-formulae (II) to (I-XII), having a carboxy group are, for example, in vivo cleavable amides thereof, such as amides formed with amines, such as ammonia, (1-4C)alkylamines, such as methylamine, [(1-4C)alkyl]2amines, such as dimethylamine, N-ethyl-N-methylamine or diethylamine, (1-4C)alkoxy-(2-4C)alkylamines, such as 2-methoxyethylamine, phenyl-(1-4C)alkylamines, such as benzylamine and amino acids, such as glycine or its esters.

[0258] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I), or subformulae (II) to (I-XII), having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, amides formed with (1-10C)alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(1-4C)alkyl)piperazin-1-ylmethyl.

[0259] The in vivo effects of the compounds of formula (I), or sub-formulas (II) to (I-XII), may be exerted in part by one or more metabolic products formed in the human or animal body following administration of the compounds of formula (I), or sub-formulas (II) to (I-XII). As described below, the in vivo effects of the compounds of formula (I), or sub-formulas (II) to (I-XII), may also be exerted as a result of metabolism of precursor compounds (prodrugs).

[0260] While the invention may relate to any compound or particular group of compounds defined herein as an optional, preferred or suitable feature, or otherwise in relation to certain particular embodiments, the invention may relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable feature or certain particular embodiment.

[0261] Suitably, the present invention excludes any individual compound that does not have biological activity as defined herein.

[0262] [Synthesis] The compounds of the present invention can be prepared by any suitable technique known in the art. Certain methods for the preparation of these compounds are further described in the accompanying examples.

[0263] In the description of synthetic methods described herein and in any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedure, can be selected by one skilled in the art.

[0264] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0265] It will be appreciated that during the synthesis of the compounds according to the invention in the processes defined herein, or during the synthesis of some of the starting materials, it may be desirable to protect some of the substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups can be introduced and subsequently removed.

[0266] For examples of protecting groups, see one of the many general texts on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (published by John Wiley & Sons, Inc.) Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such method being chosen to effect removal of the protecting group with minimal disturbance to other groups in the molecule.

[0267] Thus, for example, if the reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0268] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl, alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example, benzyloxycarbonyl, or aroyl groups, for example, benzoyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, for example, lithium hydroxide or sodium hydroxide. Alternatively, an acyl group, for example, a tert-butoxycarbonyl group, may be removed by treatment with a suitable acid, for example, hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group, for example, a benzyloxycarbonyl group, may be removed, for example, by hydrogenation over a catalyst, for example, palladium-on-carbon, or by treatment with a Lewis acid, for example, boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example, dimethylaminopropylamine, or with hydrazine.

[0269] Suitable protecting groups for hydroxy groups include, for example, acyl groups, such as alkanoyl groups, for example, acetyl, aroyl groups, for example, benzoyl, or arylmethyl groups, for example, benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, such as lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed, for example, by hydrogenation over a catalyst, for example, palladium on carbon.

[0270] A suitable protecting group for a carboxy group is, for example, an esterifying group, a methyl or ethyl group which may be removed, for example, by hydrolysis with a base such as, for example, sodium hydroxide, or a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid, for example trifluoroacetic acid, or a benzyl group which may be removed, for example, by hydrogenation over a catalyst, for example palladium on carbon.

[0271] Resins can also be used as protecting groups.

[0272] The methodology used to synthesize compounds of formula (I), or sub-formulas (II) to (I-XII), is 1 , R 2 , R 3 , R 4 , R 6 and R 10 and depending on the nature of any substituents or associated subgroups thereof. Suitable methods for their preparation are further described in the accompanying examples.

[0273] After a compound of formula (I), or sub-formulas (II) to (I-XII), has been synthesized by any one of the methods defined herein, the methods may then include the following further step: (i) removing any protecting groups present; (ii) converting a compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof It may further include:

[0274] An example of (ii) above is where a compound of formula (I) is synthesized and then R 1 , R 2 , R 3 , R 4 , R 6 and R 10 This is where one or more of the groups can be further reacted to change the nature of that group, providing alternative compounds of formula (I).

[0275] The resulting compounds of formula (I), or subformulas (II) to (I-XII), can be isolated and purified using techniques well known in the art.

[0276] Compounds of formula (I) can be synthesized by the synthetic routes set forth in the Examples section below.

[0277] [Biological activity] The pharmacological effects of the compounds of the present invention can be determined using the biological assays described in the Examples section herein.

[0278] Although the pharmacological properties of compounds of formula (I) vary with structural variations, as expected, compounds of the present invention have been found to be active in the PMS2 in vitro assay and, in some cases, also in the MLH1 in vitro assay described in the Examples section.

[0279] [Pharmaceutical composition] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0280] Compositions according to the invention may be in a form suitable for oral use (e.g. as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g. as a finely divided powder or liquid aerosol), administration by insufflation (e.g. as a finely divided powder) or parenteral administration (e.g. as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0281] The compositions according to the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0282] An effective amount of a compound according to the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0283] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain from 0.5 mg to 0.5 g (more suitably, 0.5 to 100 mg, e.g., 1 to 30 mg) of active agent, combined with an appropriate and convenient amount of excipients, which may vary, for example, from about 5 to about 98 weight percent of the total composition.

[0284] The size of an administered dose of a compound of formula I for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, according to well-known principles of medicine.

[0285] For therapeutic or prophylactic use of the compounds of the present invention, a daily dose ranging from 0.1 mg / kg to 75 mg / kg of body weight is generally administered, taking into account the need for divided doses. Generally, lower doses are administered when parenteral administration is used. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging from 0.1 mg to 30 mg / kg of body weight is generally used. Similarly, for administration by inhalation, a dose ranging from 0.05 mg to 25 mg / kg of body weight is generally used. Oral administration, particularly in tablet form, may also be appropriate. A unit dosage form typically contains about 0.5 mg to 0.5 g of the compounds of the present invention.

[0286] Therapeutic Uses and Applications The present invention provides compounds that function as inhibitors of MLH1 and / or PMS2 activity (eg, MLH1 activity or PMS2 activity or MLH1 and PMS2 activity).

[0287] Thus, compounds of formula (I), or pharmaceutically acceptable salts thereof, have potential therapeutic use in a variety of disease states in which inhibition of MLH1 and / or PMS2 activity is beneficial.

[0288] Accordingly, the present invention provides a method for treating a disease or disorder in which inhibition of MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activity) is beneficial in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0289] The present invention provides a method for inhibiting MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity, or MLH1 and PMS2 activity) in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0290] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0291] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0292] 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.

[0293] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use as a pharmaceutical.

[0294] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

[0295] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer. In a particular embodiment, the cancer is a human cancer, in particular an estrogen-positive cancer, such as breast cancer, or an androgen receptor-positive cancer, such as prostate cancer.

[0296] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in inhibiting MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity, or MLH1 and PMS2 activity). Preferably, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in inhibiting PMS2 activity; most preferably, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in inhibiting PMS2 and MLH1 activity.

[0297] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which inhibition of MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activity) is beneficial.

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

[0299] 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 the treatment of cancer.

[0300] The present invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the inhibition of MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activity).

[0301] The present invention provides the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of MLH1 and / or PMS2 activity (e.g., MLH1 activity or PMS2 activity or MLH1 and PMS2 activity) is beneficial.

[0302] The terms "proliferative disorder," "proliferative condition," and "proliferative disease" are used interchangeably herein and relate to unwanted or uncontrolled cell proliferation, either in vitro or in vivo, of excessive or abnormal cells that are unwanted, e.g., neoplastic or hyperplastic growth.

[0303] In the above aspect of the invention, the proliferative disorder is suitably cancer, and the cancer is suitably a human cancer. In particular, the compounds according to the invention are useful in the treatment of 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, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, Carney complex, central nervous system tumor, cervical cancer, colorectal cancer, Cowden disease, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, etc.). Chromoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloblastic leukemia (CRL), Myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), cancer of the nasal cavity and paranasal sinuses, nasopharyngeal carcinoma, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis type 1 and type 2, nevoid basal cell carcinoma syndrome , oral or oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumors, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas (e.g., Kaposi or soft tissue), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, vulvar cancer, Waldenström's macroglobulinemia, Werner's syndrome, Wilms' tumor, and xeroderma pigmentosum).Particular cancers of interest include hematological cancers, such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-esophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0304] The compounds of the present invention may also be used to treat triplet diseases.

[0305] Thus, a further aspect of the present invention provides a method of treating a triplet disorder (e.g., Huntington's disease (HD), myotonic dystrophy type 1 (DM1), Fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar ataxias (SCAs)) in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0306] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of a triplet disorder. In particular embodiments, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar degeneration (SCAs).

[0307] According to a further aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a triplet disorder. In particular embodiments, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar degeneration (SCAs).

[0308] [Administration route] The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic, peripheral, or local (i.e., at the desired site of action).

[0309] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., patches, plasters, etc.); transmucosally (including, e.g., patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via aerosol, e.g., through the mouth or nose, using); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); by injection, including, e.g., intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intraarticular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; parenterally, e.g., by a depot or reservoir placement, subcutaneously or intramuscularly.

[0310] [Combination therapy] The compounds of the present invention can be administered as a monotherapy, or the compounds of the present invention can be used in addition to conventional surgery or radiation therapy or chemotherapy or targeted agents, which can include one or more of the following categories: (i) As used in medical oncology, antiproliferative / antineoplastic agents and combinations thereof, for example, but not limited to, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea). antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); (ii) Cytostatic agents, such as, but not limited to, antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprolide, and buserelin), progestogens (e.g., megestrol acetate), and corticosteroids (e.g., dexamethasone, prednisone, and prednisolone), steroid hormones, including aromatase inhibitors (such as anastrozole, letrozole, vorazole, and exemestane), and inhibitors of 5α-reductase, such as finasteride; (iii) anti-invasion agents, such as, but not limited to, the c-Src kinase family inhibitor 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), bosutinib (SKI-606), and metalloproteinase inhibitors, such as marimastat, inhibitors of urokinase-type plasminogen activator receptor function or antibodies against heparanase; (iv) inhibitors of growth factor function, including, but not limited to, growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin®], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and the antibody described by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, and any growth factor or growth factor receptor antibody disclosed by I. M. Schmidt, M ... inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib (BAY43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling via MEK and / or AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors; (v) Antiangiogenic agents, including, but not limited to, those that inhibit the effects of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®) and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), and pazopanib (GW786034)]. (vi) vascular damaging agents, including, but not limited to, combretastatin A4 and compounds disclosed in WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; (viii) antisense therapy, including but not limited to those directed to the targets set forth above, e.g., ISIS2503, anti-ras antisense, etc.; (ix) Immunotherapeutic approaches, including, for example, cancer vaccines, antibodies, viruses (oncolytic viruses), and small molecule or cell therapy approaches to increase the immunogenicity of a patient's tumor cells and / or facilitate a cell-mediated anti-tumor response. Such therapies may include, but are not limited to, OX40 agonists, cGAS-STING agonists, 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 of cancer antigens by microbial vectors, direct transduction of cancer antigens into antigen-presenting cells, treatment with cancer antigen-specific immune cells (e.g., CAR-T), treatment with antibodies, antibody fragments, and antibody-drug conjugates that enable the immune system to recognize tumor cells.

[0311] Such conjoint treatment may be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the dosage ranges described hereinabove and the other pharmaceutically active agent(s) within their approved dosage ranges.

[0312] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (e.g. cancer involving a solid tumour) comprising a compound according to the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and an anti-tumour agent.

[0313] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (e.g. a cancer associated with a solid tumor), comprising a compound according to the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and any one of the anti-tumour agents set out herein above.

[0314] In a further aspect of the present invention there is provided a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer, optionally in combination with another anti-tumour agent selected from those set out herein above.

[0315] In a further aspect of the present invention there is provided a compound according to the invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, optionally in combination with a tyrosine kinase inhibitor selected from those set out herein above.

[0316] The term "combination" is understood herein to mean simultaneous, separate or sequential administration. In one aspect of the invention, "combination" means simultaneous administration. In another aspect of the invention, "combination" means separate administration. In a further aspect of the invention, "combination" means sequential administration. If administration is sequential or separate, a delay in administering the second component should not, for example, result in the loss of the beneficial effect of the combination.

[0317] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anti-tumour agent (optionally selected from those set out herein above), in association with a pharmaceutically acceptable diluent or carrier.

[0318] [Combination therapy with immunomodulation therapy] (immune checkpoint inhibitors) Immune checkpoint proteins present in immune cells and / or cancer cells (e.g., CTLA4 (also known as cytotoxic T-lymphocyte-associated protein 4 and CD152), LAG3 (also known as lymphocyte-activation gene 3 and CD223), PD1 (also known as programmed cell death protein 1 and CD279), PD-L1 (also known as programmed death-ligand 1 and CD274), TIM-3 (also known as T-cell immunoglobulin mucin-3), and TIGIT (also known as T-cell immunoreceptor with Ig and ITIM domains) are molecular targets that have been found to play an important role in regulating anti-tumor immune responses. Inhibitors of these immune checkpoint proteins (e.g., CTLA4, LAG3, PD1, PD-L1, TIM-3, and / or TIGIT inhibitors) promote anti-tumor immune responses that can be used to effectively treat some forms of cancer.

[0319] (immunostimulants) Monoclonal antibodies, bispecific antibodies, recombinant ligands, and small molecule therapeutics that bind to stimulatory receptors on immune cells can facilitate effective anti-tumor responses. Such receptors may be involved in cell-to-cell contact, for example, contact between tumor cells and immune cells or contact between two types of immune cells, while other receptors may bind to soluble factors that stimulate an immune response. In one such embodiment, the antibody, bispecific antibody, recombinant protein, or small molecule therapeutic can activate stimulatory receptors, including, but not limited to, 4-1BB, OX40, cGAS-STING, CD27, CD40, and DR3, which enhance anti-tumor immunity.

[0320] A modulator of antigen processing can facilitate the presentation of neoantigenic peptides on the cell surface to enhance effective anti-tumor responses. In one such embodiment, an inhibitor of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 can stimulate anti-tumor immunity.

[0321] In one aspect, the invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0322] In another aspect, the invention relates to the use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

[0323] In another aspect, the present invention relates to a method of treating a proliferative disorder in a subject in need thereof, comprising administering to said subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein.

[0324] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of a proliferative disorder, wherein the compound, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or an immunostimulant, or a pharmaceutically acceptable salt thereof.

[0325] In another aspect, the present invention relates to an immune checkpoint inhibitor or immunostimulant, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder, wherein the immune checkpoint inhibitor is in the case of simultaneous, separate or sequential administration with a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein.

[0326] In another aspect, the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor or an immunostimulant, or a pharmaceutically acceptable salt thereof.

[0327] In another aspect, the invention relates to the use of an immune checkpoint inhibitor or immunostimulant, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0328] In another aspect, the present invention relates to a method of treating a proliferative disorder comprising the step of sequentially, separately or simultaneously administering to a subject in need thereof therapeutically effective amounts of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof.

[0329] Any immune checkpoint inhibitor or immunostimulant may be used in a combination therapy as defined herein.

[0330] In one aspect, the immune stimulatory agent is selected from a 4-1BB stimulatory agent, an OX40 stimulatory agent, a CD27 stimulatory agent, a CD40 stimulatory agent, and a DR3 stimulatory agent. In another embodiment, the immune checkpoint inhibitor is selected from a PD1 inhibitor, a PD-L1 inhibitor, a LAG3 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, and / or a TIGIT inhibitor. In a detailed embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[0331] PD-1 is a cell surface receptor protein present on immune cells, such as T cells. PD-1 plays an important role in promoting self-tolerance by downregulating the immune system and suppressing T cell activation. PD-1 protein is an immune checkpoint that monitors autoimmunity through a dual mechanism: it promotes apoptosis (programmed cell death) of antigen-specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressor T cells).

[0332] PD-1 therefore suppresses the immune system, which prevents autoimmune diseases but can also prevent the immune system from killing cancer cells.

[0333] PD1 binds to two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest because it is highly expressed in several cancers, and its role in cancer immune evasion is therefore well established. Monoclonal antibodies targeting PD-1 to boost the immune system have been approved or are being developed for the treatment of cancer. Many tumor cells express PD-L1, the immunosuppressive PD-1 ligand; inhibiting the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate pro-oncogenic antitumor activity. This is known as immune checkpoint blockade.

[0334] Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, renal cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. They are also being investigated for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics), and MEDI-0680 (MedImmune).

[0335] Examples of drugs that block PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). These drugs have also been shown to help treat different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use in other types of cancer.

[0336] Examples of LAG3 inhibitors include BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (a bispecific DART combining PD-1 and LAG-3), GSK2831781, and LAG525.

[0337] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab.

[0338] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Lilly).

[0339] Examples of TIGIT inhibitors include tiragolumab (MTIG7192A; RG6058; Genentech / Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207 (Bristol-Myers Squibb), and ASP8374 (Astellas Pharma; Potenza Therapeutics).

[0340] In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / leratolimab, TSR-033, REGN3767, MGD013 (bispecific DART combining PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, MBG453, TSR-022, LY3321367, tiragolumab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, and / or ASP8374, or a pharmaceutically acceptable salt or solvate thereof.

[0341] [Combination therapy with DNA damage response modulators] The compounds of the present invention are particularly suitable for use in combination with agents that act as DNA damage response modulators, such as PARP inhibitors, ATM inhibitors and ATR inhibitors.

[0342] In one aspect, the present invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0343] In another aspect, the invention relates to the use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

[0344] In another aspect, the present invention relates to a method of treating a proliferative disorder in a subject in need thereof, comprising administering to said subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, as defined herein.

[0345] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of a proliferative disorder, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof.

[0346] In another aspect, the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof.

[0347] In another aspect, the present invention relates to a method of treating a proliferative disorder, comprising the step of sequentially, separately or simultaneously administering to a subject in need thereof therapeutically effective amounts of a compound as defined herein, or a pharmaceutically acceptable salt thereof, as defined herein, and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof.

[0348] Any DNA damage response modulator (eg, a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) can be used in combination therapy as defined herein.

[0349] [Probe compound] The present invention further relates to novel probe molecules formed by linking the compounds of the present invention, as defined herein, to a detection moiety by 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 test molecules to the ATP-binding site of target proteins, such as the mismatch repair (MMR) component proteins PMS2 and MLH1, or for determining the location and / or abundance of such target proteins in biological samples.

[0350] In one aspect, the present invention provides a probe compound comprising a compound of formula (I), or subformulas (II) to (I-XII), or a salt thereof, attached to a detection moiety by a linker.

[0351] In another aspect, the present invention provides a method for synthesizing a probe compound as defined herein, or a salt thereof.

[0352] In another aspect, the present invention provides the use of a probe compound as defined herein, or a salt thereof, in a displacement assay to determine the binding affinity of a test molecule to the ATP-binding site of a target protein. In one embodiment, the target protein is selected from MLH1, PMS2, or HSP90. In a particular embodiment, the target protein is MLH1 or PMS2.

[0353] 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 to the ATP-binding site of a target protein.In one embodiment, the target protein is selected from MLH1, PMS2, or HSP90.In a detailed embodiment, the target protein is MLH1 or PMS2.

[0354] In another aspect, the present invention provides an assay for determining the binding affinity of a test molecule to an ATP-binding site of a target protein, the assay comprising: (i) incubating a test molecule with a target protein in the presence of a probe compound, as defined herein, or a salt thereof; (ii) determining whether the probe compound displaces the ATP-binding site of the target protein; Includes. In one embodiment, the target protein is selected from MLH1, PMS2, or HSP90. In a particular embodiment, the target protein is MLH1 or PMS2.

[0355] In another aspect, the present invention provides a method for determining the binding affinity of a test molecule to an ATP-binding site of a target protein, the assay comprising: (i) incubating a test molecule with a target protein in the presence of a probe compound, as defined herein, or a salt thereof; (ii) determining whether the probe compound displaces the ATP-binding site of the target protein; Includes.

[0356] In another aspect, the present invention provides an assay for determining the location and / or abundance of a target protein present in a biological sample, the assay comprising: (i) contacting a biological sample with a probe compound, as defined herein, or a salt thereof; (ii) determining the location and / or amount of the compound present in the biological sample by detecting the location and / or intensity of the detection moiety of the compound of formula I present in the sample; Includes.

[0357] Suitably, the present invention provides a compound of formula B: [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , and R 6 are each as defined herein; R 10 is R as defined herein, attached to L 10 It is a base; L is a linker; Q is a detection moiety.], or a salt thereof.

[0358] The linker group L may be any suitable linker moiety that attaches the detection moiety Q to the remainder of the probe compound of formula B.

[0359] Suitably, the linker group L is 3 to 30 atoms in length, more suitably 4 to 20 atoms in length, and even more suitably 5 to 18 atoms in length. In particular groups of probe compounds of formula I or II as defined herein, L is 5 to 12 atoms in length.

[0360] The detection moiety Q can be any moiety that can detect and quantify a probe compound of Formula I. As described further below, the probe compounds of Formula I, as defined herein, are designed for use in displacement assays, whereby the ability of a test compound to displace a probe compound of Formula I from the ATP-binding site of a target protein (e.g., MLH1 or PMS2) can be used to determine the binding affinity of the test compound for the ATP-binding site of the target protein. Thus, the detection moiety Q can be any moiety that can be readily detected and quantified. In certain circumstances, the detection moiety Q is capable of detecting and quantifying any probe compound of Formula I that has been displaced (i.e., "unbound") from the ATP-binding site of the target protein. In some embodiments of the present invention, this can be accomplished by collecting any displaced or "unbound" compound of Formula I from a test sample and assaying the sample to determine how much unbound probe compound is present. This, in turn, provides an indication of how much of the probe compound present in the sample has been displaced by the test compound.

[0361] It will therefore be understood that the nature of the detection moiety Q is not critical, so long as it can be used to determine the amount of probe compound of formula I present in a sample. Those skilled in the art will be able to select an appropriate detection moiety Q and an appropriate methodology for detecting and quantifying the amount of compound of formula I in a sample, in particular for detecting the amount of probe compound of formula I that has been displaced from the ATP-binding site of a target protein by a test compound.

[0362] 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.

[0363] In embodiments in which the detection moiety Q is an oligonucleotide, biomolecule, molecular sensor, protein, or peptide, any suitable technique known in the art for detecting and quantifying the amount of oligonucleotide, biomolecule, molecular sensor, protein, or peptide present can be utilized. For example, a fluorescently labeled secondary probe can be used that can specifically bind to the detection moiety Q of a probe compound of Formula I, and after any excess secondary probe is removed, the amount of binding of the secondary probe to the detection moiety Q of the compound of Formula I can be detected and quantified, thereby allowing the amount of the probe compound of Formula I to be determined.

[0364] For example, if Q is an oligonucleotide, then a secondary probe having a suitable detectable label, e.g., a fluorophore or radiolabel, and a complementary oligonucleotide sequence capable of hybridizing to Q can be used to detect and quantify the amount of the probe compound of Formula I present in a sample (suitably the amount of probe compound displaced from the ATP-binding site of the target protein by the test compound). Similarly, if Q is a protein or peptide, then the secondary probe can be an antibody capable of selectively binding to the protein or peptide and a suitable detectable label, e.g., a fluorophore or radiolabel.

[0365] More suitably, the detection moiety Q is a fluorophore. In such cases, the compound of formula I can be used in fluorescence polarization assays. In a particular group of probe compounds of formula I, the detection moiety Q is a fluorophore selected from the group consisting of AlexaFluor dyes, cyanine dyes, fluorescein, BODIPY or BODIPY derivatives (e.g., BODIPY TMR), TAMRA, Oregon Green dyes, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red. In a further group of probe compounds of formula I, the detection moiety Q is a fluorophore selected from the group consisting of AlexaFluor-647, AlexaFluor-633, AlexaFluor-594, AlexaFluor-488, cyanine-5B, cyanine-3B, fluorescein, BODIPY TMR, TAMRA, Oregon Green 488, Oregon Green 514, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red.

[0366] Suitable salts of the probe compounds according to the present invention are, for example, sufficiently basic acid-addition salts of the compounds according to the present invention, for example, acid-addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. Furthermore, suitable salts of the compounds according to the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts or salts with organic bases.

[0367] The present invention also encompasses probe compounds according to the invention as defined herein that contain one or more isotopic substitutions, for example, H is 1 H, 2 H(D) and 3 H(T) can be in any isotopic form; C can be 12 C. 13 C and 14 It can be in any isotopic form, including C; O is 16 O and18 It can be in any isotopic form, including O; and the like.

[0368] It is also to be understood that some of the probe compounds of formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms.

[0369] It is also to be understood that some probe compounds of formula (I) may exhibit polymorphism, and that the present invention encompasses all such polymorphic forms.

[0370] Some probe compounds of formula (I) may also exist in a number of different tautomeric forms, and references to compounds of formula (I) include all such forms.

[0371] (Synthesis of probe compounds) In another aspect, the present invention provides a method of synthesizing a probe compound of formula B, or a salt thereof, as defined herein.

[0372] The probe compounds according to the present invention can be prepared by any suitable technique known in the art.

[0373] (Example) While specific embodiments of the present invention have been described herein for purposes of reference and example, various modifications will become apparent to those skilled in the art without departing from the scope of the invention as defined by the appended claims. Reference is now made to the accompanying drawings, in which: [Brief explanation of the drawings]

[0374] [Figure 1] FIG. 1 shows the reaction scheme for 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile (Example 82). [Figure 2]FIG. 1 shows the reaction scheme for 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide (Example 83). [Figure 3] FIG. 1 shows the reaction scheme for 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide (Example 85). [Figure 4] FIG. 1 shows the reaction scheme for ((2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone (Example 88). [Figure 5] FIG. 1 shows the reaction scheme for (4-(azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone (Example 89). [Figure 6] FIG. 1 shows the reaction scheme for (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone (Example 90). [Figure 7] FIG. 1 shows the reaction scheme for (4,6-dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 92). [Figure 8] FIG. 1 shows the reaction scheme for (2-ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 93). [Figure 9] FIG. 1 shows the reaction scheme for (2-(cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 94). [Figure 10]FIG. 1 shows the reaction scheme for (2-(cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 95). [Figure 11] FIG. 1 shows the reaction scheme for (2-(cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Example 96). [Figure 12] FIG. 1 shows the reaction scheme of 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 37). [Figure 13] FIG. 1 shows the reaction scheme for N,N-dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine (Intermediate 42). [Figure 14] FIG. 1 shows the reaction scheme of N,N-dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine (Intermediate 43). [Figure 15] FIG. 1 shows the reaction scheme for 1-(isoindolin-5-yl)-N,N-dimethylmethanamine hydrochloride (Intermediate 46). [Figure 16] FIG. 1 shows the reaction scheme for 4-((4-methylpiperazin-1-yl)methyl)isoindoline hydrochloride (Intermediate 48). [Example]

[0375] [Abbreviation] Boc is tert-butyloxycarbonyl DAST is diethylaminosulfur trifluoride DBU is 1,8-diazabicyclo(5.4.0)undec-7-ene DCC is dicyclohexylcarbodiimide DCE is 1,1-dichloroethane DCM is dichloromethane DEA is diethanolamine DEAD is diethyl azodicarboxylate DIAD is diisopropyl azodicarboxylate DIBAL is diisobutylaluminum hydride DIPEA is N,N-diisopropylethylamine, Hunig's base DMA is N,N-dimethylacetamide DMAP is 4-(dimethylamino)pyridine DMF is N,N-dimethylformamide DMSO is dimethyl sulfoxide. EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc is ethyl acetate h is the time HATU is N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU is (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate HOBT is N-hydroxybenzotriazole HPLC is high pressure liquid chromatography. LAH is lithium aluminum hydride IPA is isopropyl alcohol LCMS is liquid chromatography mass spectrometry LDA is lithium diisopropylamide LiHMDS is lithium bis(trimethylsilyl)amide mCPBA is meta-chloroperbenzoic acid MI is the molecular ion Min is minutes MgSO4 Anhydrous Magnesium Sulfate MW is microwave NBS is N-bromosuccinamide NCS is N-chlorosuccinamide NFOBS is N-fluoro-o-benzenedisulfonimide NFSI is N-fluorobenzenesulfonimide NHS is N-hydroxysuccinimide NIS is N-iodosuccinamide NMM is N-methylmorpholine NMP is 1-methyl-2-pyrrolidinone NMR is nuclear magnetic resonance. PdCl2(PPh3)2 is bis(triphenylphosphine)palladium chloride Pd(dppf)2Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Pd(dppf)2Cl2.DCM is the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (Pd(dba)2) is bis(dibenzylideneacetone)palladium Rbf is a round bottom flask RT is retention time. SCX-2 is a silica-based sorbent with chemically bonded propylsulfonic acid functional groups. SFC stands for supercritical fluid chromatography TBAF is tetra-n-butylammonium fluoride TBDMS is tert-butyldimethylsilyl TFAA is trifluoroacetic anhydride TFA is trifluoroacetic acid THF is tetrahydrofuran TPP is tripotassium phosphate Ts is toluenesulfonyl XPhos-Pd-G1 is 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride XPhos-Pd-G2 is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0376] [Analysis method] Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash or glass column chromatography was performed using Merck silica gel 230-400 mesh size. Flash chromatography was also performed on a combi-flash RF Teledyne Isco instrument. Preparative TLC was performed on Merck plates.

[0377] (Liquid Chromatography Mass Spectrometry) (Method-A) Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA performance mass detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 micron; Column temperature: 35 °C; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% formic acid in water (v / v):acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV; source and probe temperatures were 120 °C and 600 °C, respectively.

[0378] (Method-B) Waters Acquity with PDA detector and SQ Detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 micron; Column temperature: 35 °C; Autosampler temperature: 5 °C; Mobile phase A: 5 mM ammonium bicarbonate in water (pH = 7.35); Mobile phase B: acetonitrile; Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.5 mL / min; t = 0.2 min (97% A, 3% B) flow rate: 0.5 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.5 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 0.7 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 0.7 mL / min; Gradient to t = 3.51 min (97% A, 3% B) Flow rate: 0.5 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time: 4 min. Mass detection parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 3.25 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[0379] (Method-C) Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA performance mass detector; Column: YMC Tri-art C18, 50 x 2 mm, 1.9 micron; Column temperature: 35 °C; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% formic acid in water (v / v):acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV; source and probe temperatures were 120 °C and 600 °C, respectively.

[0380] (Method-D) Waters Acquity UPLC with quaternary solvent manager, SQ detector, and Acquity QDA mass detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 micron; Column temperature: 35 °C; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% (v / v) formic acid in water:acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ESI capillary probe, ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[0381] (Method-E) Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA performance mass detector; Column: Welch Xtimate C18, 50 × 2.1 mm, 1.8 micron; Column temperature: 35 °C; Autosampler temperature: 5 °C; Mobile phase A: 0.1% (v / v) formic acid in water (pH = 2.70); Mobile phase B: 0.1% formic acid in water (v / v):acetonitrile (10:90); Mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; Gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; Gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) flow rate: 1 mL / min B) Flow rate: 1 mL / min; gradient (97% A, 3% B) until t = 3.51 min; flow rate: 0.8 mL / min; run ended at t = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Mass detector parameters: ionization mode cycled in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV; source and probe temperatures were 120 °C and 600 °C, respectively.

[0382] (NMR) Using a Bruker Avance-400 instrument operating at 400 MHz with the solvents indicated at room temperature unless otherwise stated. 1 H nuclear magnetic resonance (NMR) spectroscopy was performed. Samples were prepared as solutions in suitable deuterated solvents and referenced to the appropriate internal non-deuterated solvent peak or to tetramethylsilane. Chemical shifts were reported in ppm (δ) downfield from tetramethylsilane. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are indicated in parts per million using conventional abbreviations for the major peak designations: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; and br, broad.

[0383] [Purification method] (Preparative purification by reversed-phase HPLC) (Preparatory HPLC Method-A) Shimadzu Prep-20-AD with a binary pump equipped with a UV / visible wavelength detector; Column: C18, 250 × 20 mm, 5 micron; Column temperature: room temperature; Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile:methanol:2-propanol (65:25:10); Mobile phase gradient details: t = 0 min (55% A, 45% B); t = 17 min (55% A, 45% B); gradient to t = 17.01 min (2% A, 98% B); t = 19 min (2% A, 98% B); gradient to t = 19.01 min (55% A, 45% B); run termination at t = 21 min (55% A, 45% B); Flow rate: 27 mL / min; Analysis time: 21 min.

[0384] (Preparatory HPLC Method-B) Shimadzu Prep-20-AD with a binary pump equipped with a UV / visible wavelength detector; Column: C18, 250 × 20 mm, 5 micron; Column temperature: room temperature; Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile; Mobile phase gradient details: t = 0 min (72% A, 28% B); t = 19 min (72% A, 28% B); gradient to t = 19.01 min (2% A, 98% B); t = 21 min (2% A, 98% B); gradient to t = 21.01 min (72% A, 28% B); run termination at t = 24 min (72% A, 28% B); Flow rate: 20 mL / min; Analysis time: 24 min. Preparative HPLC Method-C Shimadzu LC20AP purification system equipped with a UV detector. Column: YMC-Actus Triart prep, 250 x 20 mm, 5 micron, room temperature. Compounds were eluted with mobile phase A: 0.1% formic acid in Milli-Q water; mobile phase B: acetonitrile; mobile phase gradient details: t = 0 min (65% A, 35% B); gradient to t = 17 min (35% A, 65% B); gradient to t = 17.01 min (2% A, 98% B); gradient to t = 19 min (2% A, 98% B); gradient from t = 19.01 min (65% A, 35% B) to t = 21 min (65% A, 35% B); flow rate: 20 ml / min; run time: 21 min.

[0385] (Chiral preparative HPLC purification method) The enantiomeric separation of the compounds was achieved by chiral preparative HPLC purification.

[0386] Below is a list of chiral preparative HPLC purification methods and conditions used to resolve enantiomers or determine enantiomeric purity (ee).

[0387] [Table 1]

[0388] [Synthesis] Several methods for the chemical synthesis of the heterocyclic carboxamide compounds of the present application are described herein. These and / or other well-known methods may be variously modified and / or adapted to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood to be within the spirit and scope of the present application and claims. Therefore, the methods described in the following description, schemes, and examples are for illustrative purposes only and should not be construed as limiting the scope of the present disclosure.

[0389] In one approach (Scheme 1), compounds of formula [I] may be prepared by reacting a substituted aromatic carboxylic acid of formula [II] with an amine of general formula [III] in the presence of oxalyl chloride or thionyl chloride in a solvent such as DCM and a tertiary amine base such as EtN, DIPEA, or NMM. The reaction is suitably carried out at RT. After reaction workup (typically by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method A). Compounds of formula [I] may also be prepared by reacting a substituted aromatic carboxylic acid of formula [II] with an amine of general formula [III] and a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EtN, DIPEA, or NMM. After reaction workup (typically by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method B). The bistosyl-protected intermediate (from Method A or B) is then subjected to 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 suitably carried out at elevated temperature. After reaction workup (typically by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization to give a compound of general formula [I].

[0390] [ka]

[0391] Example 1: [2,4-Dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone [ka]

[0392] (Method 1) Step-1: 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 40) To a solution of 2-(pyrimidin-2-ylmethoxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 25) (0.3 g, 0.525 mmol, 1 eq) in DMF (3 mL) was added 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) under a nitrogen atmosphere at 0 °C. 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 NaSO and concentrated in vacuo. The crude material was purified by flash chromatography (product was eluted with 15% MeOH in DCM) to give 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 40) (0.19 g, 58% yield). 1 H 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 = 3.2Hz, 2H), 6.54 (d, J = LCMS (Method A): 2.204 min, MS: ES+ 624.20 (M+1)

[0393] Step-2: (2,4-Dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone To a solution of 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 40) (0.6 g, 0.481 mmol, 1 eq) in EtOH (0.6 mL) was added dropwise a solution of KOH (1.07 g, 19.24 mmol, 40 eq) in water (0.5 mL) at room temperature. The reaction mixture was heated at 80 °C for 2 h, cooled, poured into ice-cold water (80 mL), and extracted with ethyl acetate (4 × 80 mL). The combined organic layers were dried over Na SO and concentrated in vacuo. The crude material was purified by flash chromatography (product eluted with 7% MeOH in DCM) to give (2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone (0.045 g, 15% yield).

[0394] 1 H 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 = 1.6Hz, 1H), 5.92 (d, J = 2.0Hz, 1H), 7. 45 (t, J = 3.5Hz, 1H), 8.82 (d, J = 4.8Hz, 2H), 9.36 (s, 1H), 9.41 (s, 1H). LCMS (Method A): 1.033 min, MS: ES+ 316.16 (M+1)

[0395] Example 2: (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone [ka]

[0396] (Method 2) Step-1: Synthesis of 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 41) 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) was added dropwise oxalyl chloride (0.13 g, 1.02 mmol, 1.0 eq) at 0 °C under a nitrogen atmosphere. 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 give the crude acid chloride. In a separate Rbf, a solution of pyrrolidine (0.130 g, 1.83 mmol, 2.0 eq) in THF was treated with TEA (0.18 g, 1.78 mmol, 2.0 eq) at 0 °C. The crude acid chloride in DCM (5 mL) was added dropwise to the amine solution at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (20 mL) and extracted into DCM (3 × 50 mL). The combined organic layers were washed with saturated NaHCO solution (2 × 20 mL), dried over NaSO, and concentrated in vacuo to give 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 41) (0.4 g, 72% yield) as a brown oil. The crude material was used in the next step without purification.

[0397] 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 minutes, MS: ES+ 600.15 (M+1)

[0398] Step-2: (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone To a solution of 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 41) (0.2 g, 0.33 mmol, 1 eq) in MeOH (4 mL) was added KOH (0.74 g, 13.19 mmol, 40 eq) at room temperature. The reaction mixture was heated at 60 °C for 2 h. The resulting reaction mixture was poured into water (30 mL), acidified using a saturated solution of KHSO and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography (the product was eluted with 20% EtOAc in n-hexane) to give (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone (0.030 g, 30.9% yield). 1 H 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).

[0399] The following compounds were prepared according to the above method using the intermediates indicated.

[0400] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

[0401] [Example 82]: 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile (The reaction scheme is shown in FIG. 1.) 4-Bromoisoindoline hydrochloride To a stirred solution (5 mL) of tert-butyl 4-bromo-isoindoline-2-carboxylate (0.5 g, 1.67 mmol, 1.0 eq.) in DCM at 0° C., 4N HCl in dioxane (5 mL) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Reaction completion was monitored by TLC (9:1; DCM:methanol). The resulting reaction mixture was concentrated under reduced pressure, and the crude material (0.48 g) was purified by trituration with n-pentane (3×25 mL) to give the title compound (0.47 g, 2.00 mmol, yield: 100%).

[0402] 1H NMR (DMSO-d6, D2O exchange 400 MHz): δ4.48 (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).

[0403] 5-(benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) Intermediate 22 (0.5 g, 0.86 mmol, 1.0 eq.) in DMF (5 mL) was treated with HATU (0.48 g, 1.28 mmol, 1.5 eq.) and DIPEA (0.22 g, 1.71 mmol, 2.0 eq.) under a nitrogen atmosphere at 0 °C and stirred for 15 min. 4-Bromoisoindoline hydrochloride (0.17 g, 0.86 mmol, 1.0 eq.) was added, and the resulting reaction mixture was stirred at 0 °C for 1 h. Completion of the reaction was monitored by TLC (ethyl acetate:hexane 1:1). The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material (0.6 g) was purified by flash chromatography (product eluted in 2% methanol in DCM) to give the title compound (0.45 g, 0.591 mmol, yield: 69%).

[0404] LCMS (Method A): 2.860 min, MS: ES+ 764 (M+1).

[0405] <((2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone> To a stirred solution of 5-(benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.1 g, 0.13 mmol, 1.0 eq.) in EtOH:water (2 mL, 1:1) at room temperature was added aqueous KOH (0.29 g, 0.52 mmol, 40 eq. in minimal water). The resulting reaction mixture was heated to 60 °C and stirred for 2 h. Reaction completion was monitored by TLC (DCM:methanol 9:1). The resulting reaction mixture was slowly cooled to room temperature, diluted with water (10 mL), neutralized with dilute HCl, and extracted with ethyl acetate (4 × 20 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product was eluted with 6% methanol in DCM) to give the title compound (0.030 g, 0.066 mmol, yield: 50%).

[0406] 1 H NMR (DMSO-d6, 400 MHz): 1.98 (2 singlets, 3H), 4.27 - 4.57 (m, 2H), 4.63 - 4.75 (m, 2H), 4.84 - 4.95 (m, 2H), 6.30 (d, J = 2.4 Hz, 1H), 7.22 - 7.41 (m, 7H), 7.47 - 7.52 (m, 1H), 9.52 - 9.60 (m, 2H). LCMS (Method A): 2.379 min, MS: ES+ 456.4 (M+1).

[0407] 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone (0.2 g, 0.44 mmol, 1.0 eq) in DMF (2 mL) at room temperature was treated with zinc cyanide (0.027 g, 0.23 mmol, 0.54 eq), zinc powder (0.005 g, 0.088 mmol, 0.2 eq), and BINAP (0.002 g, 0.044 mmol, 0.1 eq). The reaction mixture was degassed (N gas) for 10–15 min. Pd(OAc) (0.002 mg, 0.044 mmol, 0.1 eq) was added, and the resulting reaction mixture was heated to 100 °C and stirred under microwave irradiation for 1 h. The resulting reaction mixture was slowly cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (3 × 110 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (the product was eluted in 35% EtOAc in hexanes) to give the title compound (0.05 g, 0.12 mmol. Yield: 28.38%).

[0408] 1 H NMR (DMSO-d6, 400 MHz): δ 1.99 (d, J= 8.4 Hz, 3H), 4.48 - 4.52 (m, 1H), 4.62 - 4.93 (m, 5H), 6.31 (two singlets, 1H), 7.18 - 7.28 (m, 5H), 7.45 - 7.61 (m, 1H), 7.73 - 7.79 (m, 2H), 9.57 - 9.65 (m, 2H). LCMS (Method A): 1.765 min, MS ES+ 401.2 (M+1).

[0409] [Example 83]: 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide (The reaction scheme is shown in FIG. 2.) <Methyl 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-5-carboxylate> A stirred solution of Intermediate 22 (1.2 g, 2.06 mmol, 1.0 eq) in DMF (12 mL) was treated with HATU (1.17 g, 3.09 mmol, 1.5 eq.) and DIPEA (0.53 g, 4.12 mmol, 2.0 eq.) under a nitrogen atmosphere at 0 °C and stirred for 15 min. Methyl isoindoline-5-carboxylate hydrochloride (CAS: 127168-93-8) (0.40 g, 0.22 mmol, 1.1 eq.) was added, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with ethyl acetate (120 mL) and washed with cold brine solution (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product was eluted with 0.8% methanol in DCM) to give the title compound (0.95 g, 1.28 mmol, yield: 62%).

[0410] 1 H NMR, the compound is a mixture of rotamers. (DMSO-d6, 400 MHz): δ 1.87 (s, 3H), 2.13 (s, br, 3H), 2.46 (s, br, 3H), 3.75 - 3.87 (singlet, 3H), 4.40 - 4.79 (m, 4H), 6.88 (s, 1H), 7.19 - 7.32 (m, 8H), 7.51 - 7.56 (m, 3H), 7.67 - 7.80 (m, 5H), 7.86 - 7.93 (m, 1H). LCMS (Method A): 2.969 min, 254 nm, MS: ES+ 742.2 (M+1); 3.014 min, 210 nm, MS: ES+ 742.2 (M+1).

[0411] 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-5-carboxylic acid (Intermediate 58) To a stirred solution of methyl 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-5-carboxylate (0.95 g, 1.28 mmol, 1.0 eq.) in EtOH:water (1:1) (9.5 mL) at room temperature was added an aqueous solution of NaOH (0.51 g, 12.82 mmol, 10 eq. in 0.5 mL of water). The resulting reaction mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was slowly cooled to room temperature, poured into water (125 mL), neutralized with dilute HCl, and extracted with ethyl acetate (4 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was triturated with n-pentane (3 × 30 mL) and dried using high vacuum to give the title compound (0.45 g, 1.07 mmol, yield: 84%), which was used in the next step without purification.

[0412] LCMS (Method A): 1.555 min, MS: ES+ 420.20 (M+1).

[0413] 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide To a stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-5-carboxylic acid (0.2 g, 0.47 mmol, 1.0 eq.) and (CH)NH (2 M in THF) (0.52 g, 0.52 mmol, 1.1 eq.) in THF (2 mL, 10 v) at 0 °C, T3P (50% in EtOAc) (0.22 g, 0.71 mmol, 1.5 eq.) was added, and the reaction mixture was stirred for 15 min. TEA (0.096 g, 0.95 mmol, 2.0 eq.) was added, and the reaction mixture was stirred at 0 °C for 1 h. The resulting reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (4 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC using 10% methanol in DCM to give the title compound (0.03 g, 0.06 mmol, yield: 14%).

[0414] 1H NMR (DMSO-d6, 400 MHz), the compound is a mixture of rotamers: δ 1.97 (s, 3H), 2.87(d, J= 14.4 Hz, 3H), 2.95 (m, 3H), 4.43 - 4.47 (m, 1H), 4.56 - 4.59 (m, 1H), 4.71 - 4.81 (m, 3H), 4.91 (d, J= 10.8 Hz, 1H), 6.30 (s, 1H), 7.22 - 7.43 (m, 8H), 9.54 (d, J= 16.4 Hz, 2H). LCMS (Method A): 1.563 min, MS: ES+ 447.1 (M+1).

[0415] [Example 84]: 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-5-carboxamide [ka]

[0416] 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-5-carboxamide A stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-5-carboxylic acid (0.1 g, 0.23 mmol, 1.0 eq.) (Intermediate 58) and MeNH2.HCl (0.017 g, 0.26 mmol, 1.1 eq.) in THF (1 mL) was treated with T3P (0.11 g, 0.35 mmol, 1.5 eq.) at 0 °C under a nitrogen atmosphere and stirred for 15 min. TEA (0.048 g, 0.47 mmol, 2.0 eq.) was added to the resulting reaction mixture at 0 °C and stirred for 1 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material (0.11 g) was purified by normal phase flash chromatography (silica gel: product eluted in 5.2% methanol in DCM) to give the title compound (0.017 g, 0.039 mmol, 16% yield).

[0417] 1 H NMR (DMSO-d6, 400 MHz), the compound is a mixture of rotamers: δ ppm 1.99 (s, 3H), 2.76 - 2.79 (m, 3H), 3.18 (m, 1H) 4.47 - 4.63 (m, 2H), 4.73 - 4.84 (m, 2H), 4.93 (d, J= 10.4 Hz, 2H), 6.32 (s, 1H), 7.26 - 7.40 (m, 5H), 7.68 - 7.76 (m, 1H), 7.81 - 7.97 (m, 1H), 8.93 - 8.46 (m, 1H), 9.53 - 9.58 (m, 2H). LCMS (Method A): 1.515 min, MS: ES+ 433.2 (M+1).

[0418] [Example 85]: 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide (The reaction scheme is shown in FIG. 3.) 2-(t-butyl) 4-methylisoindoline-2,4-dicarboxylate A stirred solution of t-butyl 4-bromoisoindoline-2-carboxylate (2.0 g, 6.73 mmol, 1.0 eq) (CAS: 1035235-27-8) in MeOH:DMF (10:1) (22 mL) in an autoclave at room temperature was treated with PdCl(dppf) (0.98 g, 1.28 mmol, 1.34 eq), DPPF (0.37 g, 0.673 mmol, 0.1 eq), and TEA (2.0 g, 2.01 mmol, 3.0 eq). 2 CO (gas) was applied to the reaction mixture, which was heated to 110 °C and stirred for 24 h. The reaction mixture was slowly cooled to room temperature and filtered through a celite bed. Water (60 mL) was added to the filtrate, which was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (product was eluted in 5% ethyl acetate in hexane) to give the title compound (1.5 g, 5.40 mmol. Yield: 80.6%).

[0419] 1 H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 3.86 (s, 3H), 4.62 (d, J= 10.4 Hz, 2H), 4.82 (d, J= 10.0 Hz, 2H), 7.46 (t, J= 7.6 Hz, 1H), 7.61 (t, br, 1H), 7.87 (d, J= 7.2 Hz, 1H). LCMS (Method A): 2.172 min, MS: ES+ 222.2 (M-56).

[0420] <Methylisoindoline-4-carboxylate hydrochloride> A stirred solution of 2-(t-butyl) 4-methylisoindoline-2,4-dicarboxylate (1.5 g, 5.41 mmol, 1.0 eq.) in DCM (15 mL) at room temperature was treated with 4 M HCl in dioxane (7.5 mL) at 0° C. The reaction mixture was stirred for 1 h, then evaporated under reduced pressure, and the resulting solid was triturated with n-pentane (15 mL) to give the title compound (0.95 g, 5.36 mmol, yield: 100%).

[0421] 1 H NMR (DMSO-d6, 400 MHz): δ 3.89 (s, br, 3H), 4.55 (s, br, 2H), 4.75 (s, br, 2H), 7.55 (t, J= 7.6 Hz, 1H), 7.70 (d, J= 7.2 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 10.0 (s, 2H). LCMS (Method A): 0.638 min, MS: ES+ 178.2 (M+1).

[0422] 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-4-carboxylate Four parallel batches of 0.5 g scale were performed. A stirred solution of intermediate 22 (0.5 g, 0.858 mmol, 1.0 eq) in DMF (2 mL) at 0 °C was treated with HATU (0.489 g, 1.28 mmol, 1.5 eq) and DIPEA (0.553 g, 4.29 mmol, 5.0 eq) and stirred for 10 min. Methyl isoindoline-4-carboxylate hydrochloride (0.201 g, 0.944 mmol, 1.1 eq) dissolved in DMF (1 mL) was added dropwise to the reaction mixture at 0-5 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice-cold water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (eluting the product with 3% MeOH in DCM) to give the title compound (2.0 g, 2.69 mmol yield: 78.7%), which was carried on to the next step without purification.

[0423] LCMS (Method A): 2.828 min, MS: ES+ 742.22.

[0424] 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylic acid (Intermediate 59) To a stirred solution of methyl 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-4-carboxylate (1.0 g, 1.34 mmol, 1.0 eq.) in EtOH:water (1:1) (10 mL) at room temperature was added NaOH (2.15 g, 53.92 mmol, 40 eq.). The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was cooled to 0-5 °C and acidified using a saturated solution of KHSO (pH 1-2). The aqueous layer was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was triturated with n-pentane (5 mL) and diethyl ether (5 mL) to give the title compound (0.5 g, 1.19 mmol. Yield: 88.5%) as a brown oil.

[0425] 1H NMR (DMSO-d6, 400 MHz) The compound is a mixture of rotamers: δ 1.98 (s,br, 3H), 4.11 - 4.13 (m, 2H), 4.46 - 4.72 (m, 2H), 4.85 - 5.01 (m, 2H), 6.31 (s, 1H), 7.23 - 7.96 (m, 8H), 9.51 - 9.59 (m, 2H), 13.02 (s, br, 1H). LCMS (Method A): 1.728 min, MS: ES+ 420.17 (M+1).

[0426] 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide A stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylic acid (0.250 g, 0.596 mmol, 1.0 eq) (Intermediate 59) in DMF (3 mL) at 0 °C was treated with T3P (50% in EtOAc) (0.568 mL, 0.894 mmol, 1.5 eq), TEA (0.300 g, 2.98 mmol, 5.0 eq) and stirred for 10 min. Dimethylamine hydrochloride (0.058 g, 0.715 mmol, 1.2 eq) was added to the reaction mixture at 0-5 °C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-cold water (20 mL) and extracted with ethyl acetate (3...

Claims

1. Structural formula (I), shown below: 【Chemical 1】 [In the formula, R １ and R ３ are both hydroxy; R ２ is hydrogen or fluoro; 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 selected from the group consisting of one or more R ５ａ and said (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups are optionally substituted with one or more R ５ｂ optionally substituted with; 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; R ６ is a (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or a 4- to 7-membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A): 【Chemistry 2】 (In the formula, R ７ is hydrogen or (1-3C) alkyl; n is 1 or 2; R ８ is aryl or heteroaryl, said aryl or heteroaryl being selected from one or more R ９ optionally substituted with; each R ９ is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, (2-3C) alkenyl, or (2-3C) alkynyl; R １０ is -NR １１ R １２ and R １１ and R １２ are linked together with the nitrogen atom to which they are attached such that they form a 5- to 6-membered monocyclic aromatic heterocycle or a 5- to 7-membered monocyclic heterocyclic ring fused to a benzene ring, thereby forming an 8- to 11-membered bicyclic heteroaryl ring; R １０ Any one or more of the rings present in may be one or more R １３ optionally independently substituted with; Each R １３ are halogen, cyano, oxo, epoxy and -L １ -X １ -Q １ base are independently selected from the group consisting of L １ is absent or (1-3C)alkylene; X １ is absent, or -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) ０－２ -, -C(O)-N(R １４ ) -, -N(R １４ )-C(O)-,-NR １４ -, -N(R １４ )-C(O)-NR １４ -, -SO ２ N (R １４ ) - or -N(R １４ ) SO ２ -, and R １４ each occurrence is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, (2-4C) alkenyl, and (2-4C) alkynyl; R １４ wherein any (1-4C) alkyl, (2-4C) alkenyl, or (2-4C) alkynyl is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy; Q １ is selected 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, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl; Q １ Any of (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl, or heteroaryl(1-3C)alkyl may be selected from the group consisting of one or more R １５ optionally substituted with a group; Each R １５ is 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) ２ NR １５ａ R １５ｂ , and -N(R １５ｂ )-S(O) ２ R １５ａ and R １５ａ and R １５ｂ are each independently hydrogen or (1-3C) alkyl, and R １５ａ or R １５ｂ Any (1-3C) alkyl moiety present in the group may optionally be selected from hydroxy, cyano, halogen, -OR １５ｃ , -NR １５ｃ R １５ｄ and -C(O)-R １５ｃ and R １５ｃ and R １５ｄ are independently selected from hydrogen and (1-2C) alkyl. or a pharmaceutically acceptable salt, hydrate or solvate thereof.

2. R ２ is hydrogen; R ４ is selected from the group consisting of hydrogen, fluoro, chloro(1-4C)alkyl, cyclopropyl, and cyclobutyl, and said (1-4C)alkyl is selected from the group consisting of one R ５ａ and said cyclopropyl and cyclobutyl groups are optionally substituted by one R ５ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with:

3. R ７ is hydrogen or methyl; 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1.

4. R ８ is phenyl or a 5-6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from N and O, and said phenyl or 5-6 membered heteroaryl is selected from 1, 2 or 3 R ９ 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with:

5. R ８ has the following structure: 【Chemistry 3】 [In the formula, each m １ is independently 0, 1, 2, or 3; ２ are independently 0, 1 or 2.] or a pharmaceutically acceptable salt, hydrate or solvate thereof, of the compound according to any one of claims 1 to 4.

6. R ８ has the following structure: 【Chemistry 4】 [In the formula, m １ is 0, 1, 2 or 3. ], or a pharmaceutically acceptable salt, hydrate or solvate thereof, of any one of claims 1 to 5.

7. Each R ９ is independently selected from the group consisting of hydroxy, halogen, (1-3C) alkyl, (1-3C) alkoxy, (2-3C) alkenyl and (2-3C) alkynyl, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 6.

8. R １１ and R １２ together with the nitrogen atom to which they are attached form the following ring system: 【Chemistry 5】 [In the formula, v ２ and v ３ are each independently 1 or 2; W １ is CH, N or O; each A ring is a benzene ring or a 5- to 6-membered aromatic heterocycle; Any ring may contain one or two R １３ Optionally substituted with 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

9. R １１ and R １２ together with the nitrogen atom to which they are attached form the following ring system: 【Chemistry 6】 [In the formula, v １ is 1, 2 or 3; v ２ and v ３ are each independently 1 or 2; W １ is CH, N or O; each A ring is a benzene ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 N atoms; Each R １３ａ is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl and (1-3C) alkoxy; R １３ａ wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo; each q ２ is independently 0, 1 or 2; each q ３ are independently 0 or 1.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

10. R １１ and R １２ together with the nitrogen atom to which they are attached form the following ring system: 【Chemistry 7】 [In the formula, Each q ２ is independently 0 or 1; Each q ３ is independently 0, 1 or 2; v ２ and v ３ are each independently 1 or 2; W ２ , W ３ and W ４ are each independently CH, N or O, provided that W ２ , W ３ and W ４ and 0, 1 or 2 only of are N or O; W ５ , W ６ , W ７ and W ８ are each independently CH, N, or O, with the proviso that W ５ , W ６ , W ７ and W ８ and 0, 1 or 2 only of are N or O; W ９ is N, O or CH ２ and W １０ is C or N; W １１ , W １２ and W １３ are each independently CH, N, or O, with the proviso that W １１ , W １２ and W １３ and 0, 1 or 2 only of are N or O; W １４ , W １５ , W １６ and W １７ are each independently CH, N, or O, with the proviso that W １４ , W １５ , W １６ and W １７ and 0, 1 or 2 only of are N or O; W １８ is N, O or CH ２ and W １９ is C or N; W ２０ , W ２１ , W ２２ and W ２３ are each independently CH, N, or O, with the proviso that W ２０ , W ２１ , W ２２ and W ２３ wherein only 0, 1 or 2 of the following are N or O:

11. W ２ , W ３ and W ４ are each independently CH or N, with the proviso that W ２ , W ３ and W ４ and 0, 1 or 2 only of are N; W ５ , W ６ , W ７ and W ８ are each independently CH or N, with the proviso that W ５ , W ６ , W ７ and W ８ and 0, 1 or 2 only of are N; W １１ , W １２ and W １３ are each independently CH or N, with the proviso that W １１ , W １２ and W １３ and 0, 1 or 2 only of are N; W １４ , W １５ , W １６ and W １７ are each independently CH or N, with the proviso that W １４ , W １５ , W １６ and W １７ and 0, 1 or 2 only of are N; W ２０ , W ２１ , W ２２ and W ２３ are each independently CH or N; However, W ２０ , W ２１ , W ２２ and W ２３ 11. The compound of claim 10, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein 0, 1 or 2 of are N.

12. R １１ and R １２ together with the nitrogen atom to which they are attached form the following ring system: 【Chemistry 8】 [In the formula, each q ２ is independently 0 or 1, and each q ３ is independently 0, 1 or 2; Each R １３ａ is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl and (1-3C) alkoxy; R １３ａ Any (1-3C) alkyl and (1-3C) alkoxy therein is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

13. R １１ and R １２ together with the nitrogen atom to which they are attached form the following ring system: 【Chemistry 9】 [In the formula, v ２ is 1 or 2; Ring A is a benzene ring or a 5-6 membered aromatic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N and O; Each R １３ａ is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl and (1-3C) alkoxy; R １３ａ wherein any (1-3C)alkyl and (1-3C)alkoxy is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo; each q ２ is independently 0, 1 or 2; each q ３ are independently 0 or 1.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

14. R １１ and R １２ together with the nitrogen atom to which they are attached form the following ring system: 【Chemistry 10】 [In the formula, Each q ２ is independently 0 or 1, and each q ３ is independently 0, 1 or 2; Each R １３ａ is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C) alkyl and (1-3C) alkoxy; R １３ａ Any (1-3C) alkyl and (1-3C) alkoxy therein is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

15. Each R １３ is halogen, oxo, epoxy and -L １ -X １ -Q １ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, hydrate or solvate thereof, independently selected from the group consisting of:

16. L １ is absent or is (1-2C)alkylene; X １ is not present, or -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 -, and R １４ is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C) alkyl, and (2-4C) alkenyl; R １４ wherein any (1-4C) alkyl or (2-4C) alkenyl is optionally substituted independently with one or more groups selected from the group consisting of halogen and hydroxy; Q １ is selected from the group consisting of hydrogen, (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclyl, and heteroaryl; and Q １ Any (1-6C) alkyl, (2-6C) alkenyl, aryl, heterocyclyl or heteroaryl in １５ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with a group.

17. L １ is absent or is (1-2C)alkylene; X １ is not present, or is —O—, —C(O)—, —C(O)—O—, —N(R １４ )-C(O)-, or -NR １４ -, and R １４ is independently selected at each occurrence from the group consisting of hydrogen, cyano, (1-4C) alkyl, and (2-4C) alkenyl; Q １ is selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, and 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N and O; and Q １ Any (1-4C) alkyl, (2-4C) alkenyl, phenyl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl in １５ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with a group.

18. Each R １５ is hydroxy, cyano, halogen, (1-3C) alkyl, (1-3C) alkoxy, -NR １５ａ R １５ｂ and —C(O)—NR １５ａ R １５ｂ and R １５ａ and R １５ｂ is each independently hydrogen or (1-3C) alkyl, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 17.

19. Each R １５ is selected from hydroxy, halogen, (1-3C) alkyl and —C(O)—NR １５ａ R １５ｂ and R １５ａ and R １５ｂ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each is independently hydrogen or methyl.

20. The compound is one of the following: [2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2-(cyclopentoxy)-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-piperidyl)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-piperidyl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidyl]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-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-[(1R)-1-phenylethoxy]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-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-dihydroxy-benzoyl)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-phenylethoxy)phenyl]-isoindolin-2-yl-methanone; [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone; [2,4-dihydroxy-6-(1-phenylethoxy)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; 3,4-Dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisoindolin-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)(isoindolin-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)isoindolin-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)(indolin-1-yl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(indolin-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-dimethylisoindoline-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-dimethylisoindoline-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 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from any one of:

21. 21. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of claims 1 to 20 in admixture with a pharmaceutically acceptable diluent or carrier.

22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 21, for use in therapy.

23. (i) the treatment of cancer; (ii) the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with another anti-cancer agent (e.g., a chemotherapeutic agent, an immune checkpoint inhibitor, an immunostimulatory agent, or a DNA damage repair modulator); (ii) Treatment of triplet repeat disorders A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 21, for use in

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