Inhibitor compounds

Abstract

The present invention relates to compounds of formula (I): wherein R2, R3, R4, R5, Y1, Y2, A1, A2, A3 and A4 are each as defined herein, targeting a component MLH1 of a DNA mismatch repair (MMR) process. The invention also relates to processes for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of proliferative diseases, such as cancer, as well as other diseases or conditions involving MLH1 activity (e.g., triad repeat disorders). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to certain compounds that are selective inhibitors of MLH1. The compounds of the present invention are useful for treating diseases or conditions mediated at least in part by inappropriate MLH1 activity, such as cancer. The present invention also relates to the use of these compounds as pharmaceuticals, methods for preparing them, and pharmaceutical compositions containing them. Background Art

[0002] Cancer is caused by altered cell proliferation. Exactly what causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intensive research in recent decades. This research has led to the identification of molecular targets involved in key pathways that drive this malignancy.

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

[0004] DNA mismatch repair is a bidirectional excision and resynthesis system that initiates from the 3′- or 5′-strand of a defined strand break and moves toward the mismatch; the excision trajectory extends just past the mismatch. MMR can be divided into four steps: 1) mismatch recognition by MSH proteins; 2) recruitment of MLH proteins, which attach the mismatch recognition signal to the site of initiation of the distant DNA strand break; 3) excision of the wrong 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, mismatch recognition by hMutSα (MSH2-MSH6) or hMutSβ (MSH2-MSH3) initiates the MMR pathway. Binding of hMutSα or hMutSβ to the mismatch site leads to the recruitment of MutLα (MLH1-PMS2) to form a ternary complex, whose protein-protein and protein-DNA interactions are regulated by ATP / ADP cofactors. Proliferating cell nuclear antigen (PCNA) may play a role in the recruitment of MMR proteins to the vicinity of the replication fork [1]. PCNA can also activate the latent endonuclease activity of the eukaryotic MutLα protein. After DNA cleavage, exonuclease 1 (EXO1) is recruited, which excises the newly synthesized DNA strand, and the DNA excision nick is resynthesized by DNA polymerase (Pol). When DNA resynthesis is complete, the remaining nick is ligated by DNA ligase to restore duplex integrity [2]. Consistent with this function, MMR is an important tumor suppressor pathway that is deleted in up to 40% of sporadic cancers. In addition, individuals with germline mutations in MMR genes develop cancer predisposition conditions.

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

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

[0007] MMR-deficient cancers are often and typically characterized by an accumulation of DNA mutations at a higher rate than normal cells and other tumors; for example, CMMRD tumors often have a hypermutation phenotype (>250 substitution mutations / Mb) [4]. MMR deficiency can also lead to increases or decreases in microsatellite repeat length, a phenomenon known as microsatellite instability (MSI). Cancers with more than 40% microsatellite variation (positive for two or more of five routinely tested microsatellite markers) are described as high-MSI (MSI-H). Tumors without MSI are microsatellite stable (MSS), while those with less than 40% microsatellite variation (one of five markers showing microsatellite instability) are low-MSI (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 due to insertions / deletions within coding microsatellites. In addition to altering the downstream functions of the protein, FS also creates a new amino acid sequence that serves as a substrate for antigen processing and presentation [6], stimulating the activation of the “helper” function of CD8+ T cells (class I) and CD4+ T cells (class II).

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

[10] .

[0009] It is now well established that clinical response to immune checkpoint inhibitors requires the presence of tumor neoantigens and infiltration of T cells that recognize these neoantigens. Higher neoantigen loads in patients with melanoma and non-small cell lung cancer are associated with response to CTLA-4 and PD-1 blockade [11, 12, 13]. The number of neoantigens is associated with TMB, and several large studies have demonstrated that high TMB is associated with enhanced response to checkpoint inhibitors and improved overall survival in certain tumor types, such as urothelial carcinoma

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

[19] .

[0010] Germano et al. recently proposed that MMR inactivation through MLH1 silencing increases TMB and leads to a “dynamic mutational profile” that results in a continuous turnover of neoantigens in vitro and in vivo. In mouse models, this triggers immune surveillance and leads to control of tumor growth, especially in combination with immune checkpoint inhibition

[20] . Similar results were observed after MSH2 silencing

[21] .

[0011] Guan et al. and Lu et al. reported that MLH1 deficiency leads to cytoplasmic DNA release, cGAS-STING pathway activation, and IFN-β production. Guan et al. demonstrated that MLH1 deficiency leads to DNA overexpression, RPA depletion, chromosomal instability, and cytoplasmic DNA accumulation

[22] . Lu et al. reported that sensing of cytoplasmic DNA by the cGAS-STING pathway contributes to the clinical benefit of immunotherapy in patients with MMR-deficient tumors

[23] . These reports suggest that ablation of MMR activity may trigger beneficial immune activation by activating the cGAS-STING pathway.

[0012] Therefore, there is a strong biological and clinical rationale for the need for inhibitors targeting MLH1 proteins, which are key components of DNAMMR-mediated antitumor immune responses.

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

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

[24] .

[0015] Therefore, there is a need for compounds that selectively target the MLH1 component of the DNA MMR process to treat triplet repeat diseases. The present invention is designed in view of the foregoing. The present invention is designed in view of the foregoing.

[0016] References

[0017] 1.Martin-Lopez, JVand R.Fishel, The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome. FamCancer, 2013.12(2): p159-68.

[0018] 2. Liu, D., G. Keijzers, and LJ Rasmussen, DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res, 2017.773: p.174-187.

[0019] 3.Lynch,H.T.,et al.,Review of the Lynch syndrome:history,moleculargenetics,screening,differential diagnosis,and medicolegal ramifications.ClinGenet,2009.76(1):p.1-18.

[0020] 4.Shlien,A.,et al.,Combined hereditary and somatic mutations ofreplication error repair genes result in rapid onset of ultra-hypermutatedcancers.Nat Genet,2015.47(3):p257-62

[0021] 5.Sehgal,R.,et al.,Lynch syndrome:an updated review.Genes(Basel),2014.5(3):p.497-507

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

[0023] 7.Gubin,M.M.and R.D.Schreiber,CANCER.The odds of immunotherapysuccess.Science,2015.350(6257):p.158-9.

[0024] 8.Kloor,M.and M.von Knebel Doeberitz,The Immune Biology ofMicrosatellite-Unstable Cancer.Trends Cancer,2016.2(3):p.121-133.

[0025] 9.Giannakis,M.,et al.,Genomic Correlates of Immune-Cell Infiltratesin Colorectal Carcinoma.Cell Rep,2016.17(4):p.1206.

[0026] 10.Lemery,S.,P.Keegan,and R.Pazdur,First FDA Approval Agnostic ofCancer Site-When a Biomarker Defines the Indication.N Engl J Med,2017.377(15):p.1409-1412.

[0027] 11.Le,D.T.,et al.,PD-1 Blockade in Tumors with Mismatch-RepairDeficiency.N Engl J Med,2015.372(26):p.2509-20.

[0028] 12.Rizvi,N.A.,et al.,Cancer immunology.Mutational landscapedetermines sensitivity to PD-1 blockade in non-small cell lungcancer.Science,2015.348(6230):p.124-8.

[0029] 13.Van Allen,E.M.,et al.,Genomic correlates of response to CTLA-4blockade in metastatic melanoma.Science,2015.350(6257):p.207-211.

[0030] 14.Rosenberg,J.E.,et al.,Atezolizumab in patients with locallyadvanced and metastatic urothelial carcinoma who have progressed followingtreatment with platinum-based chemotherapy:a single-arm,multicentre,phase 2trial.Lancet,2016.387(10031):p.1909-20.

[0031] 15.Hellmann,M.D.,et al.,Genomic Features of Response to CombinationImmunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.CancerCell,2018.33(5):p.843-852 e4.

[0032] 16.Rizvi,H.,et al.,Molecular Determinants of Response to Anti-Programmed Cell Death(PD)-1 and Anti-Programmed Death-Ligand 1(PD-L1)Blockadein Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing.J Clin Oncol,2018.36(7):p.633-641.

[0033] 17.Carbone,D.P.,et al.,First-Line Nivolumab in Stage IV or RecurrentNon-Small-Cell Lung Cancer.N Engl J Med,2017.376(25):p.2415-2426.

[0034] 18.Hellmann,M.D.,et al.,Nivolumab plus Ipilimumab in Lung Cancer witha High Tumor Mutational Burden.N Engl J Med,2018.378(22):p.2093-2104.

[0035] 19.Hellmann,M.D.,et al.,Tumor Mutational Burden and Efficacy ofNivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell LungCancer.Cancer Cell,2018.33(5):p.853-861e4.

[0036] 20.Germano,G.,et al.,Inactivation of DNA repair triggers neoantigengeneration and impairs tumour growth.Nature,2017.552(7683):p.116-120.

[0037] 21.Mandal,R.,et al.,Genetic diversity of tumors with mismatch repairdeficiency influences anti-PD-1immunotherapy response.Science,2019.364(6439):p.485-491.

[0038] 22.Guan J.,et al.,MLH1 deficiency-triggered DNA hyperexcision byexonuclease 1activates the cGAS-STING pathway.Cancer Cell.2021,39(1),109-121,

[0039] 23. 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.

[0040] 24. Manley, K., et al., Msh2 deficiency prevents in vivo somaticinstability of the CAG repeat in Huntington disease transgenic mice. NatGenet, 1999.23(4): p.471-3. Summary of the Invention

[0041] According to a first aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0042] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

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

[0044] According to another aspect of the present invention, there is provided a method for treating a disease or condition in which MLH1 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0045] According to another aspect of the present invention, there is provided a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

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

[0047] According to another aspect of the present invention, there is provided a method of treating a triad disorder (e.g., Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA) and spinocerebellar ataxia (SCA)) in a patient in need of such treatment, said method comprising 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.

[0048] According to another aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in therapy.

[0049] According to another aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use as a medicament.

[0050] According to another aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in treating a proliferative disease.

[0051] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in treating cancer. In a particular embodiment, the cancer is a human cancer.

[0052] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in the treatment of a triplet disorder. In a specific embodiment, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA) and spinocerebellar ataxia (SCA).

[0053] According to another aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting MLH1 activity.

[0054] According to another aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or condition in which MLH1 activity is implicated.

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

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

[0057] According to another 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 preparation of a medicament for treating a triplet disorder. In a specific embodiment, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA) and spinocerebellar ataxia (SCA).

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

[0059] According to another 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 preparation of a medicament for treating a disease or condition involving MLH1 activity.

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

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

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

[0063] In the above aspects of the invention, the proliferative disease is suitably a cancer, and the cancer is suitably a human cancer. In particular, the compounds of the invention will be used to treat any cancer for which mismatch repair inhibition and / or cGAS / STING pathway activation is beneficial. Any suitable cancer may be targeted (e.g., adenoid cystic carcinoma, adrenal tumors, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, biliary tract cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney syndrome, central nervous system tumors, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer). , eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor-GIST, germ cell 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 cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemias (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B cell Prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal and sinus cancer, pharyngeal cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis type 1 and type 2, nevoid basal cell carcinoma syndrome, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas (e.g., Kaposi sarcoma or soft tissue), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic cancer, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom macroglobulinemia, Werner syndrome, Wilms tumor, and xeroderma pigmentosum).Particular cancers of interest include hematological cancers, such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastroesophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, bile duct cancer, central nervous system cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0064] Probe compounds

[0065] The present invention also relates to the discovery of a series of novel probe compounds that effectively bind to the ATP binding site of MLH1. These probe compounds can be used in assays and methods for evaluating the binding affinity of a test compound for the ATP binding site of MLH1. Furthermore, these probe compounds can be used to determine the location and / or amount of MLH1 in a biological sample.

[0066] Thus, in another aspect, the present invention provides a probe compound of formula (I) as defined herein, or a salt thereof, wherein R 12 or R 13 One of them is a group LQ or L as defined herein x -X.

[0067] In another aspect, the present invention provides a method for synthesizing a probe compound of formula (I) or a salt thereof as defined herein.

[0068] In another aspect, the present invention provides use of a probe compound of formula (I) or a salt thereof in a displacement assay to determine the binding affinity of a test molecule to the ATP binding site of MLH1.

[0069] In another aspect, the present invention provides a probe compound of formula (I) or a salt thereof for use in a displacement assay to determine the binding affinity of a test molecule to the ATP binding site of MLH1.

[0070] In another aspect, the present invention provides an assay for determining the binding affinity of a test molecule to the ATP binding site of MLH1, the assay comprising:

[0071] (i) incubating the test molecule with the target protein in the presence of a probe compound of formula (I) as defined herein, or a salt thereof; and

[0072] (ii) determining whether the probe compound of formula (I) is displaced from the ATP binding site of the target protein.

[0073] In another aspect, the present invention provides a method for determining the binding affinity of a test molecule to the ATP binding site of MLH1, the assay comprising:

[0074] (i) incubating the test molecule with the target protein in the presence of a probe compound of formula (I) as defined herein, or a salt thereof; and

[0075] (ii) determining whether the probe compound of formula (I) is displaced from the ATP binding site of the target protein.

[0076] In another aspect, the present invention provides an assay for determining the location and / or amount of MLH1 present in a biological sample, the assay comprising:

[0077] (i) contacting a biological sample with a probe compound of formula (I) as defined herein, or a salt thereof; and

[0078] (ii) determining the location and / or amount of the compound of formula (I) present in the sample by detecting the location and / or intensity of the detection moiety of the compound of formula (I) present in the biological sample.

[0079] In another aspect, the present invention provides an assay for determining the location and / or amount of MLH1 present in a biological sample, the assay comprising:

[0080] (i) contacting a biological sample with a probe compound of formula (I) or a salt thereof, wherein R 12 or R 13 One of them is a group L as defined herein x -X; and

[0081] (ii) contacting the biological sample with a detection moiety Q or a compound of formula Q-L2-Y as defined herein, which is capable of reacting with a functional group X present on the compound of formula (I) to form a compound of formula (I) in situ in the biological sample, wherein R 12 or R 13 One is a group LQ as defined herein;

[0082] (iii) determining the location and / or amount of the compound of formula (I) present in the sample by detecting the location and / or intensity of the detection portion Q of the probe compound of formula (I) present in the biological sample.

[0083] In another aspect, the present invention provides a method for determining the location and / or amount of MLH1 present in a biological sample, the method comprising:

[0084] (i) contacting a biological sample with a probe compound of formula (I) as defined herein, or a salt thereof; and

[0085] (ii) determining the location and / or amount of the compound of formula (I) present in the sample by detecting the location and / or intensity of the detection portion Q of the probe compound of formula (I) present in the biological sample.

[0086] In another aspect, the present invention provides a method for determining the location and / or amount of MLH1 present in a biological sample, the method comprising:

[0087] (i) contacting a biological sample with a probe compound of formula (I) or a salt thereof, wherein R 12 or R 13 One of them is a group L as defined herein x -X; and

[0088] (ii) contacting the biological sample with a detection moiety Q or a compound of formula Q-L2-Y as defined herein, which is capable of reacting with the functional group X present on the probe compound of formula (I) to form a compound of formula (I) in situ in the biological sample, wherein R 12 or R 13 One is a group LQ as defined herein;

[0089] (iii) determining the location and / or amount of the compound of formula (I) present in the sample by detecting the location and / or intensity of the detection moiety Q of the compound of formula (I) present in the biological sample.

[0090] Features, including optional, suitable and preferred features, associated with one aspect of the present invention may also be features, including optional, suitable and preferred features, associated with any other aspect of the present invention. DETAILED DESCRIPTION

[0091] definition

[0092] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0093] It should be understood that references to "treating" or "treating" include preventing as well as alleviating established symptoms of a condition. Thus, "treating" or "managing" a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition that develop in a human who may be suffering from or susceptible to the condition, disorder, or condition but who does not yet experience or exhibit clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) relieving or alleviating the disease or at least one of its clinical or subclinical symptoms, i.e., causing regression of the condition, disorder, or condition.

[0094] "Therapeutically effective amount" refers to an amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal being treated. It should be understood that, for example, in humans or other mammals, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount can be the amount required by the guidelines of the U.S. Food and Drug Administration (FDA) or equivalent foreign regulatory agencies for a specific disease and the subject being treated. It should be understood that determining a suitable dosage form, dosage, and route of administration is within the ordinary skill level of the pharmaceutical and medical fields.

[0095] As used herein, "subject" and "patient" alone or in combination with one or more other terms refer to animals (e.g., mammals), particularly humans. Suitably, "subject" and "patient" can be non-human animals (e.g., livestock and domestic pets) or humans.

[0096] As used herein, "pharmaceutically acceptable," alone or in combination with another term or terms, refers to a material that is generally chemically and / or physically compatible with the other ingredients (e.g., with respect to a formulation), and / or generally physiologically compatible with its recipient (e.g., a subject).

[0097] In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," refer only to the straight-chain form, and references to individual branched-chain alkyl groups, such as "isopropyl," refer only to the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl.

[0098] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

[0099] "Alkylene" is an alkyl group that is positioned between two other chemical groups and serves to connect them. Thus, "(1-6C)alkylene" refers to a straight-chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms, such as methylene (-CH2-), ethylene isomers (-CH(CH3)- and -CH2CH2-), propylene isomers (-CH(CH3)CH2-, -CH(CH2CH3)-, -C(CH3)2-, and -CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and the like.

[0100] The term "alkenyl" refers to straight and branched chain alkyl groups containing 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present in the group. Examples of alkenyl groups include ethenyl, propenyl, and but-2,3-enyl, and include all possible geometric (E / Z) isomers.

[0101] The term "alkynyl" refers to straight and branched chain alkyl groups containing 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present in the group. Examples of alkynyl groups include ethynyl and propynyl.

[0102] "(m-nC)cycloalkyl" refers to 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.

[0103] The term "alkoxy" refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0104] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (eg, fluorine) atom. Examples of haloalkyl groups include -CH2F, -CHF2, and -CF3.

[0105] The term "halogen" refers to fluorine, chlorine, bromine and iodine, suitably fluorine, chlorine and bromine, more suitably fluorine and chlorine.

[0106] The term "carbocyclyl," "carbocyclic," or "carbocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spirocyclic bicyclic carbon-containing ring system. The monocyclic carbocycle contains about 3 to 12 (suitably 3 to 7) ring atoms. The bicyclic carbocycle contains 6 to 17 member atoms in the ring, suitably 7 to 12 member atoms. The bicyclic carbocycle can be a fused, spirocyclic, or bridged ring system. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, and spiro[3.3]heptyl.

[0107] The term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic heterocyclic ring system. The monocyclic heterocycle comprises about 3 to 12 (suitably 3 to 7) ring atoms and has 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. The bicyclic heterocycle contains 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. The bicyclic heterocycle can be a fused ring, spiro ring or bridged ring system. The example of heterocyclic group includes cyclic ethers, such as oxiranyl, oxetane, tetrahydrofuranyl, dioxane and substituted cyclic ethers. Nitrogen-containing heterocycle includes, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro 2H-thiopyran and hexahydrothiophene. Other heterocycles include dihydrooxathioxo, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrooxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholino, thiomorpholino, tetrahydropyrimidinyl, dioxolane, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Examples include sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholino, such as tetrahydrothiophene 1,1-dioxide and thiomorpholino 1,1-dioxide. The heterocycle may contain 1 or 2 oxo (=O) or thio (=S) substituents. Suitable values ​​for heterocyclic groups with 1 or 2 oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclic groups are saturated monocyclic 3-7 membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholino, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholino, thiomorpholino 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by the skilled artisan, any heterocyclic ring may be attached to another group via any suitable atom, such as via a carbon or nitrogen atom. However, references to piperidinyl or morpholino herein refer to the piperidin-1-yl or morpholino-4-yl ring attached through the ring nitrogen.

[0108] A "bridged ring system" refers to a ring system in which two rings share two or more atoms, see, e.g., Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclyl ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinuclidine.

[0109] "Spirocyclic bicyclic ring system" means two ring systems that share a common spirocyclic carbon atom, i.e., a heterocyclic ring is connected to another carbocyclic or heterocyclic ring through a common spirocyclic carbon atom. Examples of spirocyclic 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.

[0110] As used herein, "aromatic," alone or in combination with one or more other terms, refers to monocyclic and polycyclic ring systems containing 4n + 2π electrons, where n is an integer. Aromatic is understood to mean 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 can be substituted or unsubstituted.

[0111] As used herein, "non-aromatic," alone or in combination with one or more other 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.

[0112] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring containing one or more (e.g., 14, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes monovalent and divalent species. Examples of heteroaryls are monocyclic and bicyclic groups containing 5-12 ring members, more typically 5-10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by fused 5- and 6-membered rings or two fused 6-membered rings. Each ring can contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino substituents on the ring, will be less than five.

[0113] Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene (triazenyl), benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazoline "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are non-aromatic saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolyl, 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.

[0114] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0115] Examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0116] The bicyclic heteroaryl group may be, for example, a group selected from:

[0117] a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0118] a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

[0119] a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0120] a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

[0121] a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0122] a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0123] an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0124] an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0125] an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0126] a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0127] an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0128] a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

[0129] a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

[0130] a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and

[0131] A cyclopentyl ring fused to a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 ring heteroatoms.

[0132] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl.

[0133] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0134] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a specific embodiment, aryl is phenyl.

[0135] This specification also uses several compound terms to describe groups containing more than one functionality. For example, (3-6C)cycloalkyl(m-nC)alkyl includes (m-nC)alkyl substituted with (3-6C)cycloalkyl.

[0136] The term "optionally substituted" refers to both substituted and unsubstituted groups, structures or molecules. The term "wherein R 1 One / any CH, CH2, CH3 group or heteroatom (i.e. NH) in the group is optionally substituted" suitably represents R 1 (Any) hydrogen radical in a group is replaced by the relevant specified group.

[0137] When optional substituents are selected from "one or more" groups, it is understood that this definition includes all substituents selected from one specific group or substituents selected from two or more specific groups. In some embodiments, one or more refers to one, two, or three. In another embodiment, one or more refers to one or two. In a specific embodiment, one or more refers to one.

[0138] The phrase "compounds of the invention" refers to those compounds disclosed herein, both generically and specifically.

[0139] "About," when used herein in connection with a measurable value, such as an amount or a period of time, is intended to include reasonable variation from that value, for example, to account for experimental error in measuring the value.

[0140] Compound

[0141] In one aspect, the present invention relates to a compound or a pharmaceutically acceptable salt thereof having the structural formula (I) shown below:

[0142]

[0143] in

[0144] R 2 is hydrogen or fluorine;

[0145] R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy;

[0146] R 4 is selected from hydrogen, halogen or cyano;

[0147] or R 3 and R 4 Connection formation:

[0148] a fused 5- or 6-membered carbocyclic or heterocyclic ring;

[0149] fused benzene rings; or

[0150] a 5-membered or 6-membered heteroaryl ring;

[0151] each of which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy;

[0152] R 5 It is R 6 OR 6 ;

[0153] where R 6 is (1-6C)alkyl, (3-8C)cycloalkyl, a 4-7 membered heterocyclyl ring containing one heteroatom selected from N, O or S, phenyl or a 5- or 6-membered heteroaryl; each of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy;

[0154] or a group having a structure according to formula (A) shown below:

[0155]

[0156] in

[0157] R 7 is hydrogen or (1-3C)alkyl;

[0158] n is 1 or 2;

[0159] R 8 is (3-8C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy;

[0160] Y1 is a bond, -CH2-, -CH2-CH2- or -C(=O)-;

[0161] Y2 is -CH2-, -C(=O)-, or -CHR y2a -、-CH2-CH2-、-CH2-CHR y2b -or-CHR y2a -CH2-; where R y2a is selected from halogen, cyano, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, and R y2b is selected from halogen, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, provided that when Y1 is a bond, Y2 is -CH2-CH2-, -CH2-CHR y2b -or-CHR y2a -CH2-;

[0162] A1 is selected from N, CH or CR 11 ;

[0163] A2 is selected from N, CH or CR 12 ;

[0164] A3 is selected from N, CH or CR 13 ;

[0165] A4 is selected from N, CH or CR 14 ;

[0166] The condition is that only one or two of A1, A2, A3 or A4 can be N;

[0167] R 11 is cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy group is optionally substituted by one or more halogen or (1-2C)alkoxy groups;

[0168] or R 11 Yes-(CHR z ) a -Z 11 ,

[0169] in:

[0170] R z is hydrogen or methyl;

[0171] a is 0 or 1; and

[0172] Z11 Yes-OR 15 、R 15a 、-NR 16 R 17 、-C(O)NR 16 R 17 or -NR 18 C(O)R 19 ;

[0173] in

[0174] R 15 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-7C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-8 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 2;

[0175] R 15a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-7C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-8 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 2;

[0176] R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-7C)cycloalkyl,

[0177] (CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w )c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0, 1 or 2;

[0178] or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0179] R 18 is hydrogen or (1-2C)alkyl;

[0180] R 19 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR x ) d -(3-7C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4-8 membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl];

[0181] where R x is hydrogen or methyl; and d is 0 or 1;

[0182] where R 11 、R 15 、R 15a 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0183] R 12 Select one of the following options:

[0184] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0185] (ii) When R 11 Not a group -(CHRz ) a -Z 11 When R 12 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0186] R 12 Yes-(CHR v ) d -Z 12 ,

[0187] in:

[0188] R v is hydrogen or methyl;

[0189] d is 0 or 1; and

[0190] Z 12 Yes-OR 20 、R 20a 、-NR 21 R 22 、-C(O)NR 21 R 22 or -NR 23 C(O)R 24 ;

[0191] where R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen or methyl, and e is 0, 1, 2 or 3;

[0192] R 20a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHRu ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen or methyl, and e is 0, 1, 2 or 3;

[0193] R 21 and R 22 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl], wherein R q is hydrogen or methyl, and f is 0 or 1;

[0194] or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0195] R 23 is hydrogen or (1-2C)alkyl;

[0196] R 24 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4-8 membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], wherein R p is hydrogen or methyl, and g is 0 or 1;

[0197] where R 12 、R 20 、R 20a 、R 21 、R 22 、R 23 or R 24 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more Ra replace;

[0198] R 13 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or

[0199] R 13 Yes-(CHR o ) h -Z 13 ,

[0200] in:

[0201] R o is hydrogen or methyl;

[0202] h is 0 or 1; and

[0203] Z 13 Yes-OR 25 、R 25a 、-NR 26 R 27 、-C(O)NR 26 R 27 or -NR 28 C(O)R 29 ;

[0204] where R 25 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n is hydrogen or methyl, and i is 0, 1 or 2;

[0205] R 25a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n )i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above;

[0206] R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl], wherein R m is hydrogen or methyl, and j is 0 or 1;

[0207] or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0208] R 28 is hydrogen or (1-2C)alkyl;

[0209] R 29 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-8 membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], wherein R l is hydrogen or methyl, and k is 0 or 1;

[0210] where R 13 、R 25 、R 25a 、R 26 、R 27 、R 28 or R 29 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace;

[0211] R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0212] R 14 Yes-(CHR k ) m -Z 14 ,

[0213] where R k is hydrogen or methyl;

[0214] wherein m is 0 or 1; and

[0215] Z 14 Yes-OR 30 、R 30a 、-NR 31 R 32 、-C(O)NR 31 R 32 or -NR 33 C(O)R 34 ;

[0216] where R 30 is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4-8 membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], wherein R j is hydrogen or methyl, and o is 0 or 1;

[0217] R 30a is (1-4C)alkyl, (3-7C)cycloalkyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4-8 membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], wherein R j is hydrogen or methyl, and o is 0 or 1;

[0218] R 31 and R 32Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR i ) p -(3-7C)cycloalkyl, -(CHR i ) p -[4- to 8-membered heterocyclyl] or -(CHR i ) p -[5- or 6-membered heteroaryl], wherein R i is hydrogen or methyl, and p is 0 or 1;

[0219] or R 31 and R 32 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0220] R 33 is hydrogen or (1-2C)alkyl;

[0221] R 34 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR h ) q -(3-7C)cycloalkyl, -(CHR h ) q -[4-8 membered heterocyclyl] or -(CHR h ) q -[5- or 6-membered heteroaryl], wherein R h is hydrogen or methyl, and q is 0 or 1;

[0222] where R 14 、R 30 、R 30a 、R 31 、R 32 、R 33 or R 34 , or when R 31 and R 32 Any ring formed when connected, optionally with one or more R a replace;

[0223] And each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-4C)alkyl or a group

[0224] -L 1 -X 1 -Q 1

[0225] in:

[0226] L 1 Absent or (1-2C)alkylene;

[0227] X 1 Not present or selected from -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-, where R 14 is hydrogen or (1-2C)alkyl;

[0228] Q 1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl or (3-6C)cycloalkyl; wherein when Q 1 When Q is (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl or (3-6C)cycloalkyl, 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy;

[0229] And where R 12 or R 13 One of the groups is optionally:

[0230] -LQ

[0231] or

[0232] -L x -X

[0233] Where L is the linker;

[0234] L x It is a joint;

[0235] X is a functional group; and

[0236] Q is the detection part.

[0237] In another aspect, the present invention provides a probe compound of formula I as defined herein, wherein R 2 、R 3 、R 4 、R5 、R 6 ,Y1,Y2,A1,A2,A3,A4,R 11 、R 12 、R 13 and R 14 Each has any of the definitions provided above, provided that R 12 or R 13 One of the groups is:

[0238] -LQ

[0239] or

[0240] -L x -X

[0241] Where L is the linker;

[0242] L x It is a joint;

[0243] X is a functional group; and

[0244] Q is the detection part.

[0245] In a specific group of compounds of the present invention, R 2 It's hydrogen.

[0246] In another group of compounds of the present invention, the compound is a compound of formula (II) to (I-XLV) as shown below or a pharmaceutically acceptable salt thereof:

[0247]

[0248]

[0249]

[0250]

[0251]

[0252] where R 3 、R 4 、R 5 , Y1, Y2, A1, A2, A3, A4 and any associated substituents each have any of the definitions given herein.

[0253] Specific compounds of the present invention include, for example, compounds of formula (I), or any one of formulas (II) to (I-XLV) above, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, and where present, R 2 、R 3 、R 4、R 5 ,Y1,Y2,A1,A2,A3,A4,L,L x , X, Q and any related substituents each have any meaning as defined above or below in paragraphs (1) to (161):

[0254] (1)R 2 It is hydrogen;

[0255] (2)R 2 It is fluorine;

[0256] (3)R 4 is selected from hydrogen, fluorine, chlorine or cyano;

[0257] (4)R 4 is selected from hydrogen, fluorine or chlorine;

[0258] (5) R4 is selected from hydrogen or fluorine;

[0259] (6)R 4 It is hydrogen;

[0260] (7)R 4 It is fluorine;

[0261] (8)R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy;

[0262] (9)R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy;

[0263] (10)R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy; or R 3 and R 4connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy or (1-2C)fluoroalkoxy;

[0264] (11)R 3 is selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0265] (12)R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy;

[0266] (13)R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring;

[0267] (14)R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered cycloalkyl ring;

[0268] (15)R 4 is hydrogen and R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy;

[0269] (16)R 4 is hydrogen and R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy; or R3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy;

[0270] (17)R 4 is hydrogen and R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy or (1-2C)fluoroalkoxy;

[0271] (18)R 4 is hydrogen and R 3 is selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0272] (19)R 4 is hydrogen and R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy;

[0273] (20)R 4 is hydrogen and R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring;

[0274] (21)R 4 is hydrogen and R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 connected to form a fused 5- or 6-membered cycloalkyl ring;

[0275] (22)R5 Yes-OR 6 , where R 6 As defined in any of paragraphs (25) to (36) above or below;

[0276] (23)R 5 Yes-OR 6 , where R 6 As defined in any of paragraphs (33), (34), (35) or (36) above or below;

[0277] (24)R 5 Yes-OR 6 , where R 6 As defined above or in paragraph (36) below;

[0278] (25)R 6 is (1-6C)alkyl, (3-6C)cycloalkyl or a 4-6 membered heterocyclyl ring containing one heteroatom selected from N, O or S, each of which is optionally substituted by a substituent selected from the group consisting of hydroxy, cyano, halogen, amino, amido(1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;

[0279] or a group having a structure according to formula (A) shown below:

[0280]

[0281] in

[0282] R 7 is hydrogen or (1-3C)alkyl;

[0283] n is 1 or 2;

[0284] R 8 is (3-7C)cycloalkyl, phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy;

[0285] (26)R 6 is (1-6C)alkyl, (3-6C)cycloalkyl or a 4-6 membered heterocyclyl ring containing one heteroatom selected from N, O or S,

[0286] or a group having a structure according to formula (A) shown below:

[0287]

[0288] in

[0289] R 7 is hydrogen or (1-3C)alkyl;

[0290] n is 1 or 2;

[0291] R 8 is (3-8C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or 9- or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy, and wherein any 4- to 6-membered heterocyclyl optionally contains 1 or 2 additional bridge atoms;

[0292] (27)R 6 is a (1-6C)alkyl group or a group having a structure according to formula (A) shown below:

[0293]

[0294] in

[0295] R 7 is hydrogen or (1-3C)alkyl;

[0296] n is 1 or 2;

[0297] R 8 is (3-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or 9- or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein any 4- to 6-membered heterocyclyl optionally contains 1 or 2 additional bridge atoms;

[0298] (28)R 6 is a (1-4C)alkyl group or a group having a structure according to formula (A) shown below:

[0299]

[0300] in

[0301] R 7 is hydrogen or (1-2C)alkyl;

[0302] n is 1 or 2;

[0303] R 8 is (3-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or 9- or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein any 4- to 6-membered heterocyclyl optionally contains 1 additional bridge atom;

[0304] (29)R 6 is a (1-4C)alkyl group or a group having a structure according to formula (A) shown below:

[0305]

[0306] in

[0307] R 7 is hydrogen or methyl;

[0308] n is 1;

[0309] R 8 is (3-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or 9- or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein any 4- to 6-membered heterocyclyl optionally contains 1 additional bridge;

[0310] (30)R 6 is a (1-3C)alkyl group or a group having a structure according to formula (A) shown below:

[0311]

[0312] in

[0313] R 7 is hydrogen or methyl;

[0314] n is 1;

[0315] R 8 is (3-6C)cycloalkyl, phenyl, 6-membered heterocyclyl, 6-membered heteroaryl, or 9-membered or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R9 independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

[0316] (31)R 6 is methyl, ethyl or a group having a structure according to formula (A) shown below:

[0317]

[0318] in

[0319] R 7 is hydrogen or methyl;

[0320] n is 1;

[0321] R 8 is (3-6C)cycloalkyl, phenyl, 6-membered heterocyclyl, 6-membered heteroaryl, or 9-membered or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

[0322] (32)R 6 is methyl or a group having a structure according to formula (A) shown below:

[0323]

[0324] in

[0325] R 7 is hydrogen or methyl;

[0326] n is 1;

[0327] R 8 is cyclopropyl, cyclohexyl, phenyl, 6-membered heterocyclic group, pyridyl, benzimidazole or quinoline, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

[0328] (33)R 6 is methyl or a group having a structure according to formula (A) shown below:

[0329]

[0330] in

[0331] R 7 is hydrogen or methyl;

[0332] n is 1;

[0333] R 8 is cyclopropyl, cyclohexyl, phenyl, pyridyl, benzimidazole or quinoline, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of fluoro, chloro, methyl or methoxy;

[0334] (34)R 6 is methyl or a group having a structure according to formula (A) shown below:

[0335]

[0336] in

[0337] R 7 is hydrogen or methyl;

[0338] n is 1;

[0339] R 8 is cyclopropyl or phenyl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of fluoro, chloro, methyl or methoxy;

[0340] (35)R 6 is methyl or a group having a structure according to formula (A) shown below:

[0341]

[0342] in

[0343] R 7 is hydrogen or methyl;

[0344] n is 1;

[0345] R 8 is cyclopropyl or phenyl;

[0346] (36)R 6 is a group having a structure according to formula (A) shown below:

[0347]

[0348] in

[0349] R 7 is hydrogen or methyl;

[0350] n is 1;

[0351] R 8 It is phenyl;

[0352] (37) Y1 is -CH2-;

[0353] (37a) Y1 is a bond, -CH2- or -CH2-CH2-;

[0354] (38) Y1 is -C(=O)-;

[0355] (39) Y2 is -CH2-, -CHR y2a -、-CH2-CH2-、-CH2-CHR y2b -or-CHR y2a -CH2-; where R y2a is selected from halogen, cyano, methyl, CF3 or hydroxymethyl, and R y2b is selected from halogen, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, provided that when Y1 is a bond, Y2 is -CH2-CH2-, -CH2-CHR y2b -or-CHR y2a -CH2-;

[0356] (40) Y2 is -CH2-, -CHR y2a -、-CH2-CH2-、-CH2-CHR y2b -or-CHR y2a -CH2-; where R y2a is selected from halogen, methyl or hydroxymethyl, and R y2b is selected from halogen, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, provided that when Y1 is a bond, Y2 is -CH2-CH2-, -CH2-CHR y2b -or-CHR y2a -CH2-;

[0357] (41) Y2 is -CH2-, -CH2-CH2- or -CH2-CHRy2b; wherein R y2b is selected from halogen, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, provided that when Y1 is a bond, Y2 is -CH2-CH2- or -CH2-CHR y2b -;

[0358] (42) Y2 is -CH2- or -CH2-CH2-, provided that when Y1 is a bond, Y2 is -CH2-CH2-;

[0359] (43) Y2 is -CH2-;

[0360] (44) Y2 is -CH2-CH2-;

[0361] (45) A1 is selected from CH or CR 11 ;

[0362] (46) A1 is CH;

[0363] (47)A1 is CR 11 ;

[0364] (48) A2 is selected from CH or CR 12 ;

[0365] (49)A2 is N;

[0366] (50) A2 is CH;

[0367] (51)A2 is CR 12 ;

[0368] (52) A3 is selected from CH or CR 13 ;

[0369] (53)A3 is N;

[0370] (54) A3 is CH;

[0371] (55)A3 is CR 13 ;

[0372] (56) A4 is selected from CH or CR 14 ;

[0373] (57)A4 is N;

[0374] (58) A4 is CH;

[0375] (59)A4 is CR 14 ;

[0376] (60) A1 is selected from N, CH or CR 11 , where R 11 As defined in any of paragraphs (68) to (86) above or below;

[0377] A2 is selected from N, CH or CR 12 , where R 12 As defined in any of paragraphs (87) to (96) above or below;

[0378] A3 is selected from N, CH or CR 13 , where R 13 As defined in any of paragraphs (97) to (101) above or below;

[0379] A4 is selected from N, CH or CR 14 , where R 14 As defined in any of paragraphs (102) to (105) above or below;

[0380] The condition is that only one of A1, A2, A3 or A4 can be N;

[0381] (61) A1 is selected from CH or CR 11 , where R 11 As defined above or in paragraph (74) below;

[0382] A2 is selected from N, CH or CR 12 , where R 12 As defined above or below (89);

[0383] A3 is selected from N, CH or CR 13 , where R 13 As defined above or in paragraph (98) below;

[0384] A4 is selected from N, CH or CR 14 , where R 14 As defined above or in paragraph (102) below;

[0385] The condition is that only one of A2, A3 or A4 can be N;

[0386] (62)A1 is CR 11 , where R 11 As defined above or in paragraph (80) below;

[0387] A2 is selected from N, CH or CR 12 , where R 12 As defined above or in paragraph (91) below;

[0388] A3 is selected from N, CH or CR 13 , where R 13 As defined above or in paragraph (99) below;

[0389] A4 is selected from N, CH or CR 14 , where R 14 As defined above or in paragraph (103) below;

[0390] The condition is that only one of A2, A3 or A4 can be N;

[0391] (63)A1 is CR 11 , where R 11 As defined above or in paragraph (68) below;

[0392] A2 is selected from N or CH;

[0393] A3 is selected from N, CH or CR 13 , where R 13 As defined above or in paragraph (97) below;

[0394] A4 is selected from N or CH;

[0395] The condition is that only one of A2, A3 or A4 can be N;

[0396] (64)A1 is CR 11 , where R 11 As defined above or in paragraph (74) below;

[0397] A2 is CH;

[0398] A3 is CH or CR 13 , where R 13 As defined above or in paragraph (99) below;

[0399] A4 is CH;

[0400] (65)A1 is CR 11 , where R 11 As defined above or in paragraph (80) below;

[0401] A2 is CH;

[0402] A3 is CH;

[0403] A4 is CH;

[0404] (66) A1 is CH;

[0405] A2 is CR 12 , where R 12 As defined above or in paragraph (87) below;

[0406] A3 is CH;

[0407] A4 is CH;

[0408] (67) A1 is CH;

[0409] A2 is CH;

[0410] A3 is CR 13 , where R 13 As defined above or in paragraph (97) below;

[0411] A4 is CH;

[0412] (68)R 11 is cyano, halogen or (1-2C)alkyl optionally substituted by one or more halogen or (1-2C)alkoxy;

[0413] or -(CHR z ) a -Z 11 ,

[0414] in:

[0415] R z is hydrogen or methyl;

[0416] a is 0 or 1; and

[0417] Z 11 Yes-OR 15 、-NR 16 R 17 、-C(O)NR 16 R 17 or -NR 18 C(O)R 19 ;

[0418] in

[0419] R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0420] R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1;

[0421] or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

[0422] R 18is hydrogen or (1-2C)alkyl;

[0423] R 19 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclic group, 5 or 6 membered heteroaryl, -(CHR x ) d -(3-6C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4-6 membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl];

[0424] where R x is hydrogen or methyl; and d is 0 or 1;

[0425] where R 11 、R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0426] where R a As defined in any of paragraphs (106) to (114) above or below;

[0427] (69)R 11 is cyano, halogen or optionally substituted by one or more R a substituted (1-2C)alkyl; or

[0428] -(CHR z ) a -Z 11 ,

[0429] where R z is hydrogen or methyl;

[0430] where a is 0 or 1; and

[0431] Z 11 Yes-OR 15 、-NR 16 R 17 、-C(O)NR 16 R 17 or -NR 18 C(O)R 19 ;

[0432] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0433] R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1 or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

[0434] R 18 is hydrogen or (1-2C)alkyl;

[0435] R 19 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclic group, 5 or 6 membered heteroaryl, -(CHR x ) d -(3-6C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4-6 membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl];

[0436] where R x is hydrogen or methyl; and d is 0 or 1;

[0437] where R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0438] where R a As defined in any of paragraphs (106) to (114) above or below;

[0439] (70)R 11 is cyano, fluoro, chloro or (1-2C)alkyl optionally substituted by one or more fluoro, chloro or (1-2C)alkoxy groups;

[0440] or -(CHR z ) a -Z 11 ,

[0441] where R z is hydrogen or methyl;

[0442] where a is 0 or 1; and

[0443] Z 11 Yes-OR 15 、-NR 16 R 17 、-C(O)NR 16 R 17 or -NR 18 C(O)R 19 ;

[0444] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0445] R 16 and R 17Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1

[0446] or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

[0447] R 18 is hydrogen or (1-2C)alkyl;

[0448] R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5- or 6-membered heteroaryl, or -(CHR x ) d -(3-6C)cycloalkyl;

[0449] where R x is hydrogen or methyl; and d is 0 or 1;

[0450] where R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0451] where R a As defined in any of paragraphs (106) to (114) above or below;

[0452] (71)R 11 is cyano or -(CHR z ) a -Z 11 ,

[0453] where R z is hydrogen or methyl;

[0454] where a is 0 or 1; and

[0455] Z 11 Yes-OR 15 、-NR 16 R 17 or -NR 18 C(O)R 19 ;

[0456] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0457] R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl,

[0458] (CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1

[0459] or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

[0460] R 18 is hydrogen or (1-2C)alkyl;

[0461] R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5- or 6-membered heteroaryl, or -(CHR x ) d -(3-6C)cycloalkyl;

[0462] where R x is hydrogen or methyl; and d is 0 or 1;

[0463] where R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0464] where R a As defined in any of paragraphs (106) to (114) above or below;

[0465] (72)R 11 Yes-(CHR z ) a -Z 11 ,

[0466] where R z is hydrogen;

[0467] where a is 0 or 1; and

[0468] Z 11 Yes-OR 15 、-NR 16 R 17 or -NR 18 C(O)R 19 ;

[0469] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0470] R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c-(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1

[0471] or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

[0472] R 18 is hydrogen or (1-2C)alkyl;

[0473] R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl;

[0474] where R x is hydrogen or methyl; and d is 0 or 1;

[0475] where R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0476] where R a As defined in any of paragraphs (106) to (114) above or below;

[0477] (73)R 11 Yes-(CHR z ) a -Z 11 ,

[0478] where R z is hydrogen or methyl;

[0479] where a is 0 or 1; and

[0480] Z 11 Yes-OR 15 、-NR 16 R 17 or -NR 18 C(O)R 19 ;

[0481] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, carbon-linked 4-6 membered heterocyclic group, 5 or 6 membered heteroaryl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, b is 0 or 1;

[0482] where R 16 is hydrogen, and R 17 selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1;

[0483] or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

[0484] R 18 is hydrogen or (1-2C)alkyl;

[0485] R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl;

[0486] where R x is hydrogen or methyl; and d is 0 or 1;

[0487] where R 15 、R 17 、R 18 or each of R19, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace;

[0488] where R a As defined in any of paragraphs (106) to (114) above or below;

[0489] (74)R 11 Yes-(CHR z ) a -Z 11 ,

[0490] where R z is hydrogen or methyl;

[0491] where a is 0 or 1; and

[0492] Z 11 Yes-OR 15 or -NR 16 R 17 ;

[0493] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0494] where R 16 is hydrogen, and R 17 selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1;

[0495] where R 15 or R 17 Each optionally represented by one or more R a replace;

[0496] where R a As defined in any of paragraphs (106) to (114) above or below;

[0497] (75)R 11 Yes-(CHR z ) a -Z 11 ,

[0498] where R z is hydrogen or methyl;

[0499] where a is 0 or 1; and

[0500] Z 11 Yes-OR 15 or -NR 16 R 17 ;

[0501] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1;

[0502] where R 16 is hydrogen, and R 17 selected from (3-6C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1;

[0503] where R 15 or R 17 Each optionally represented by one or more R a replace;

[0504] where R a As defined in any of paragraphs (106) to (114) above or below;

[0505] (76)R11 Yes-(CHR z ) a -Z 11 ,

[0506] where R z is hydrogen or methyl;

[0507] where a is 0 or 1; and

[0508] Z 11 Yes-OR 15 or -NR 16 R 17 ;

[0509] where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, carbon-linked 4-6 membered heterocyclic group, 5 or 6 membered heteroaryl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, b is 0 or 1;

[0510] where R 16 is hydrogen, and R 17 is selected from (3-6C)cycloalkyl, phenyl, carbon-linked 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl;

[0511] Each R 15 or R 17 Optionally one or more R a replace;

[0512] where R a As defined in any of paragraphs (106) to (114) above or below;

[0513] (77)R 11 Yes-(CHR z ) a -Z 11 ,

[0514] where R z is hydrogen or methyl;

[0515] where a is 0 or 1; and

[0516] Z 11 Yes-OR 15 or -NR 16 R 17 ;

[0517] where R 15is (1-4C)alkyl, (3-6C)cycloalkyl, carbon-linked 4- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl;

[0518] where R 16 is hydrogen, and R 17 is selected from (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5- or 6-membered heteroaryl, -CH2-(3-6C)cycloalkyl, -CH2-phenyl, -CH2-[4-8 membered heterocyclyl] or -CH2-[5- or 6-membered heteroaryl];

[0519] Each R 15 or R 17 Optionally one or more R a replace;

[0520] where R a As defined in any of paragraphs (106) to (114) above or below;

[0521] (78)R 11 Yes-(CHR z ) a -Z 11 ,

[0522] where R z is hydrogen or methyl;

[0523] where a is 0 or 1; and

[0524] Z 11 Yes-OR 15 or -NR 16 R 17 ;

[0525] where R 15 is (1-4C)alkyl, (4-6C)cycloalkyl, carbon-linked 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl;

[0526] where R 16 is hydrogen, and R 17 is selected from (4-6C)cycloalkyl, phenyl, carbon-linked 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -CH2-(4-6C)cycloalkyl, -CH2-phenyl, -CH2-[4-6-membered heterocyclyl] or -CH2-[5- or 6-membered heteroaryl];

[0527] Each R 15 or R 17 Optionally one or more R a replace;

[0528] where R a As defined in any of paragraphs (106) to (114) above or below;

[0529] (79)R 11 Yes-(CHR z ) a -Z 11 ,

[0530] where R z is hydrogen;

[0531] where a is 0 or 1; and

[0532] Z 11 Yes-NR 16 R 17 ;

[0533] where R 16 is hydrogen, and R 17 selected from (3-6C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1;

[0534] where R 17 Optionally, one or more R a replace;

[0535] where R a As defined in any of paragraphs (106) to (114) above or below;

[0536] (80)R 11 Yes-(CHR z ) a -Z 11 ,

[0537] where R z is hydrogen;

[0538] where a is 0 or 1; and

[0539] Z 11 Yes: -OR 15 , where R 15 is (1-4C)alkyl, optionally substituted by one or more R a replace;

[0540] where R aAs defined in any of paragraphs (106) to (114) above or below; or -NHR 17 , where R 17 Selected from:

[0541] (i) Groups of formula (A), (B), (C) or (D):

[0542]

[0543] in

[0544] W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl;

[0545] R W1C 、R W1D and R W1E is selected from hydrogen or methyl, or R W1C and R W1D or R W1D and R W1E or R W1E and W1 are linked so that together with the carbon atom to which they are linked they form a (4-6C)cycloalkyl ring, a 5- or 6-membered heterocyclyl ring, or a 5- or 6-membered heteroaryl ring, each of which is optionally substituted by one or more R a replace;

[0546] W2 is selected from O, NR w2 , S or S(O)2, where R w2 is selected from hydrogen, (1-4C)alkyl or (2-4C)alkanoyl;

[0547] and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace;

[0548] where R a As defined in any of paragraphs (106) to (114) above or below;

[0549] (ii) a bridged form of the above formulae (C) and (D), optionally selected from one of the following formulae (E) to (J):

[0550]

[0551] wherein Y4 is selected from -CH2-, -CH2CH2-,

[0552] and each of formulae (E), (F), (G), (H) and (J) is optionally replaced by one or more R areplace;

[0553] where R a As defined in any of paragraphs (106) to (114) above or below;

[0554] (iii) a group of the following formula (K), (L) or (M):

[0555]

[0556] in:

[0557] R W3 is selected from hydrogen or (1-2C)alkyl;

[0558] W3, W4 and W5 are selected from N or CR w4 , where R w4 is hydrogen, halogen, (1-2C)alkyl or (1-2C)alkoxy;

[0559] One of W6 and W7 is N, the other is CR w5 , W8 is N or CR w5 , where R w5 is hydrogen, halogen, (1-2C)alkyl or (1-2C)alkoxy;

[0560] W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one or two of them are N;

[0561] (81)R 11 Yes-(CHR z ) a -Z 11 ,

[0562] where R z is hydrogen;

[0563] where a is 0 or 1; and

[0564] Z 11 Yes: -OR 15 , where R 15 is (1-4C)alkyl; or

[0565] -NHR 17 , where R 17 Selected from:

[0566] (i) Groups of formula (A), (B), (C) or (D):

[0567]

[0568]

[0569] in

[0570] W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl;

[0571] R W1C 、R W1D and R W1E is selected from hydrogen or methyl, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace;

[0572] W2 is selected from O, NR w2 , S or S(O)2, where R w2 is selected from hydrogen, (1-4C)alkyl or (2-4C)alkanoyl;

[0573] and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace;

[0574] where R a As defined in any of paragraphs (106) to (114) above or below;

[0575] (ii) a bridged form of the above formulae (C) and (D), optionally selected from one of the following formulae (E) to (J):

[0576]

[0577] wherein Y4 is selected from -CH2-, -CH2CH2-,

[0578] and each of formulae (E), (F), (G), (H) and (J) is optionally replaced by one or more R a replace;

[0579] where R a As defined in any of paragraphs (106) to (114) above or below;

[0580] (iii) a group of the following formula (K), (L) or (M):

[0581]

[0582] in:

[0583] R W3 is selected from hydrogen or (1-2C)alkyl;

[0584] W3, W4 and W5 are selected from N or CR w4 , where R w4 is hydrogen, halogen, (1-2C)alkyl or (1-2C)alkoxy;

[0585] One of W6 and W7 is N, the other is CR w5 , W8 is N or CR w5 , where R w5 is hydrogen, halogen, (1-2C)alkyl or (1-2C)alkoxy;

[0586] W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one or two of them are N;

[0587] (82)R 11 Yes-(CHR z ) a -Z 11 ,

[0588] where R z is hydrogen;

[0589] where a is 0 or 1; and

[0590] Z 11 Yes: -OR 15 , where R 15 is (1-3C)alkyl; or

[0591] -NHR 17 , where R 17 Selected from:

[0592] (i) Groups of formula (A), (B), (C) or (D):

[0593]

[0594] in

[0595] W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl;

[0596] R W1C 、R W1D and R W1E Selected from hydrogen, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace;

[0597] W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0598] and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace;

[0599] where R a As defined in any of paragraphs (106) to (114) above or below;

[0600] (ii) a bridged form of the above formulae (C) and (D), optionally selected from one of the following formulae (E) to (J):

[0601]

[0602]

[0603] wherein Y4 is selected from -CH2-, -CH2CH2-,

[0604] and each of formulae (E), (F), (G), (H) and (J) is optionally replaced by one or more R a replace;

[0605] where R a As defined in any of paragraphs (106) to (114) above or below;

[0606] (iii) a group of the following formula (K), (L) or (M):

[0607]

[0608] in:

[0609] R W3 is selected from hydrogen or (1-2C)alkyl;

[0610] W3, W4 and W5 are selected from N or CH;

[0611] One of W6 and W7 is N, the other is CH, and W8 is N or CH;

[0612] W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one of them is N

[0613] (83)R 11 Yes-(CHR z ) a -Z 11 ,

[0614] where R z is hydrogen;

[0615] where a is 0 or 1; and

[0616] Z 11 Yes: -OR 15 , where R 15 is (1-2C)alkyl; or

[0617] -NHR 17 , where R 17 is a group of formula (A), (B), (C) or (D):

[0618]

[0619] in

[0620] W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl;

[0621] R W1C 、R W1D and R W1E Selected from hydrogen, or R W1C and R W1Dor R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace;

[0622] W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0623] and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace;

[0624] where R a as defined in any of paragraphs (106) to (114) above or below; or

[0625] A group of the following formula (K), (L) or (M):

[0626]

[0627] in:

[0628] R W3 is selected from hydrogen or methyl;

[0629] W3, W4 and W5 are selected from N or CH;

[0630] One of W6 and W7 is N, the other is CH, and W8 is N or CH;

[0631] W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one of them is N

[0632] (84)R 11 It's Z 11 ,

[0633] Z 11 Yes: -OR 15 , where R 15 is (1-2C)alkyl; or

[0634] -NHR 17 , where R 17 Selected from:

[0635] Groups of formula (A), (B), (C), (D) or (M):

[0636]

[0637] in

[0638] W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl;

[0639] R W1C 、R W1D and R W1E Selected from hydrogen, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace;

[0640] W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0641] and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace;

[0642] where R a As defined in any of paragraphs (106) to (114) above or below;

[0643] W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one of them is N;

[0644] (85)R 11 It's Z 11 ,

[0645] Z 11 Yes: -OR 15 , where R 15 is methyl; or

[0646] -NHR 17 , where R 17 Selected from:

[0647] Groups of formula (B), (C), (D) or (M):

[0648]

[0649] in

[0650] W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0651] and each of formulae (B), (C) and (D) is optionally substituted with oxo (=O);

[0652] W9, W 10 、W 11 and W 12 is selected from N or CH; provided that W9, W 10 、W 11 and W 12 Only one of them is N;

[0653] (86)R 11 It's Z 11 ,

[0654] Z 11 Yes: -OR 15 , where R 15 is methyl; or

[0655] -NHR 17 , where R 17 Selected from:

[0656] Groups of formula (B), (C) or (D):

[0657]

[0658] in

[0659] W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0660] and each of formulae (B), (C) and (D) is optionally substituted with oxo (=O);

[0661] W9, W 10 、W 11 and W 12is selected from N or CH; provided that W9, W 10 、W 11 and W 12 Only one of them is N;

[0662] (87)R 12 Select one of the following options:

[0663] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0664] (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0665] R 12 Yes-(CHR v ) d -Z 12 ,

[0666] where R V is hydrogen or methyl;

[0667] where d is 0 or 1; and

[0668] Z 12 Yes-OR 20 、R 20a 、-NR 21 R 22 、-C(O)NR 21 R 22 or -NR 23 C(O)R 24 ;

[0669] where R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHRu ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen or methyl, and e is 0, 1 or 2;

[0670] R 20a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen or methyl, and e is 0, 1 or 2;

[0671] R 21 and R 22 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl], wherein R q is hydrogen or methyl, and f is 0 or 1;

[0672] or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0673] R 23 is hydrogen or (1-2C)alkyl;

[0674] R 24 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g-phenyl, -(CHR p ) g -[4-8 membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], wherein R p is hydrogen or methyl, and g is 0 or 1;

[0675] where R 20 、R 20a 、R 21 、R 22 、R 23 or R 24 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace;

[0676] where R a As defined in any of paragraphs (106) to (114) above or below;

[0677] (88)R 12 Select one of the following options:

[0678] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0679] (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0680] R 12 Yes-(CHR v ) d -Z 12

[0681] where R V is hydrogen or methyl;

[0682] where d is 0 or 1; and

[0683] Z12 Yes-OR 20 、R 20a 、-NR 21 R 22 、-C(O)NR 21 R 22 or -NR 23 C(O)R 24 ;

[0684] where R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen, and e is 0, 1

[0685] or 2;

[0686] R 19 is (1-4C)alkyl, (4-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl,

[0687] R 21 and R 22 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl], wherein R q is hydrogen or methyl, and f is 0 or 1;

[0688] or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0689] R 23 is hydrogen or methyl;

[0690] R24 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4-8 membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], wherein R p is hydrogen or methyl, and g is 0 or 1;

[0691] where R 20 、R 20a 、R 21 、R 22 、R 23 or R 24 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace;

[0692] where R a As defined in any of paragraphs (106) to (114) above or below;

[0693] (89)R 12 Select one of the following options:

[0694] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0695] (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0696] R 12 Yes-(CHR v ) d -Z12

[0697] where R v is hydrogen;

[0698] where d is 0 or 1; and

[0699] Z 12 Yes-OR 20 、R 20a 、-NR 21 R 22 、-C(O)NR 21 R 22 or -NR 23 C(O)R 24 ;

[0700] where R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl;

[0701] R 19 is (1-4C)alkyl, (4-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl,

[0702] R 21 and R 22 each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4- to 8-membered heterocyclyl, or a 5- or 6-membered heteroaryl;

[0703] or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0704] R 23 It is hydrogen;

[0705] R 24 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4- to 8-membered heterocyclyl, or 5- or 6-membered heteroaryl;

[0706] where R 20 、R 20a 、R 21 、R 22 or R 24 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace;

[0707] where R a As defined in any of paragraphs (106) to (114) above or below;

[0708] (90)R 12 Select one of the following options:

[0709] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0710] (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0711] R 12 Yes-(CHR v ) d -Z 12

[0712] where R v is hydrogen;

[0713] where d is 0 or 1; and

[0714] Z 12 Yes-OR 20 、-NR 21 R 22 or -C(O)NR 21 R 22 ;

[0715] where R 20 is (1-4C)alkyl;

[0716] R 21 and R 22 each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4- to 8-membered heterocyclyl, or a 5- or 6-membered heteroaryl;

[0717] or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0718] where R 20 、R 21 or R22 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace;

[0719] where R a As defined in any of paragraphs (106) to (114) above or below;

[0720] (91)R 12 Select one of the following options:

[0721] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0722] (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0723] R 12 Yes-(CHR v ) d -Z 12

[0724] where R v is hydrogen;

[0725] where d is 0 or 1; and

[0726] Z 12 Yes-NR 21 R 22 ;

[0727] where R 21 and R 22 each independently selected from hydrogen, (1-3C)alkyl, (4-6C)cycloalkyl, phenyl, a carbon-linked 4- to 6-membered heterocyclyl, or a 5- or 6-membered heteroaryl;

[0728] or R 21 and R 22connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0729] where R 21 or R 22 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace;

[0730] where R a As defined in any of paragraphs (106) to (114) above or below;

[0731] (92)R 12 Select one of the following options:

[0732] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0733] (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0734] R 12 Yes-(CHR v ) d -Z 12

[0735] where R v is hydrogen;

[0736] where d is 1; and

[0737] Z 12 Yes-NR 21 R 22 , where R 21 and R 22 are each independently selected from hydrogen or methyl;

[0738] (93)R 12 Select one of the following options:

[0739] (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0740] (ii) When R 11 Not-(CHR z ) a -Z 11 When the group is 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups;

[0741] (94)R 12 is selected from halogen, (1-2C)alkyl or (1-2C)alkoxy;

[0742] (95)R 12 is selected from chlorine, fluorine, (1-2C)alkyl or (1-2C)alkoxy;

[0743] (96)R 12 is a (1-2C)alkoxy group;

[0744] (97)R 13 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or

[0745] R 13 Yes-(CHR o ) h -Z 13 ,

[0746] where R o is hydrogen or methyl;

[0747] where h is 0 or 1; and

[0748] Z 12 Yes-OR 25 、R 25a 、-NR 26 R 27 、-C(O)NR 26 R 27 or -NR 28 C(O)R 29 ;

[0749] where R 25 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n is hydrogen or methyl, and i is 0 or 1;

[0750] R 25a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above;

[0751] R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl], wherein R m is hydrogen or methyl, and j is 0 or 1;

[0752] or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0753] R 28 is hydrogen or methyl;

[0754] R 29 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-8 membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], wherein R l is hydrogen or methyl, and k is 0 or 1;

[0755] where R 25 、R 25a 、R 26 、R 27 or R 29 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace;

[0756] where R a As defined in any of paragraphs (106) to (114) above or below;

[0757] (98)R 13 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or

[0758] R 13 Yes-(CHR o ) h -Z 13 ,

[0759] where R o is hydrogen or methyl;

[0760] where h is 0 or 1; and

[0761] Z 12 Yes-OR 25 、R 25a 、-NR 26 R 27 、-C(O)NR 26 R 27 or -NR 28 C(O)R 29 ;

[0762] where R 25 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n is hydrogen or methyl, and i is 0 or 1;

[0763] R 25a is (1-4C)alkyl, (4-6C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(4-6C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-6 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above;

[0764] R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl], wherein R m is hydrogen or methyl, and j is 0 or 1;

[0765] or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0766] R 28 is hydrogen or methyl;

[0767] R29 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-8 membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], wherein R l is hydrogen or methyl, and k is 0 or 1;

[0768] where R 25 、R 25a 、R 26 、R 27 or R 29 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace;

[0769] where R a as defined in any of paragraphs (106) to (114) above or below; or

[0770] (99)R 13 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or

[0771] R 13 Yes-(CHR o ) h -Z 13 ,

[0772] where R o is hydrogen or methyl;

[0773] where h is 0 or 1; and

[0774] Z 12 Yes-OR 25 、R 25 、-NR 25 R 27 or -C(O)NR 26 R 27 ;

[0775] where R 25 is (1-4C)alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR n )i -[4-8 membered heterocyclyl], wherein

[0776] R n is hydrogen or methyl, i is 0 or 1;

[0777] R 25a is (1-3C)alkyl 5- or 6-membered heteroaryl, -(CHR n ) i -(4-6C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-6 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above;

[0778] R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR m ) j -[4- to 8-membered heterocyclyl], wherein R m is hydrogen or methyl, and j is 0 or 1;

[0779] or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0780] where R 25 、R 25a 、R 26 or R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace;

[0781] where R a As defined in any of paragraphs (106) to (114) above or below;

[0782] (100)R 13 Yes-(CHR o ) h -Z 13 ,

[0783] where R o is hydrogen or methyl;

[0784] where h is 0 or 1; and

[0785] Z12 Yes-OR 25 、R 25 or -NR 26 R 27 ;

[0786] where R 25 is (1-4C)alkyl;

[0787] R 25a is (1-2C)alkyl 5-membered heteroaryl, -(CHR n ) i -[6-membered heterocyclyl] or -(CHR n ) i -[5-membered heteroaryl], where R n and i is as defined above;

[0788] R 26 and R 27 are each independently selected from hydrogen or (1-6C)alkyl;

[0789] or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0790] where R 25 、R 25 、R 26 、R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace;

[0791] where R a As defined in any of paragraphs (106) to (114) above or below;

[0792] (101)R 13 Yes-(CHR o ) h -Z 13 ,

[0793] where R o is hydrogen;

[0794] where h is 0 or 1; and

[0795] Z 12 Yes-OR 25 or -NR 26 R 27 ;

[0796] where R 25 is (1-2C)alkyl;

[0797] R 26 and R 27 are each independently selected from hydrogen or (1-2C)alkyl;

[0798] where R 25 、R 26 、R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace;

[0799] where R a As defined in any of paragraphs (106) to (114) above or below;

[0800] (102)R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0801] R 14 Yes-(CHR k ) m -Z 14 ,

[0802] where R k is hydrogen or methyl;

[0803] wherein m is 0 or 1; and

[0804] Z 12 Yes-OR 30 、-NR 31 R 32 、-C(O)NR 31 R 32 or -NR 33 C(O)R 34 ;

[0805] where R 30 is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4-8 membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], wherein R j is hydrogen or methyl, and o is 0 or 1;

[0806] R31 and R 32 each independently selected from hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, a carbon-linked 4-8 membered heterocyclyl, a 5- or 6-membered heteroaryl, -(CHRi)p-(3-7C)cycloalkyl, -(CHRi)p-[4- to 8-membered heterocyclyl], or -(CHRi)p-[5- or 6-membered heteroaryl], wherein Ri is hydrogen or methyl, and p is 0 or 1;

[0807] or R 31 and R 32 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0808] R 33 is hydrogen or methyl;

[0809] R 34 is (1-6C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR h ) q -(3-7C)cycloalkyl, -(CHR h ) q -[4-8 membered heterocyclyl] or -(CHR h ) q -[5- or 6-membered heteroaryl], wherein R h is hydrogen or methyl, q is 0 or 1;

[0810] where R 30 、R 31 、R 32 or R 34 , or when R 31 and R 32 Any ring formed when connected, optionally with one or more R a replace;

[0811] where R a As defined in any of paragraphs (106) to (114) above or below;

[0812] (103)R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0813] R 14 Yes-(CHR k ) m -Z 14 ,

[0814] where R kis hydrogen;

[0815] wherein m is 0 or 1; and

[0816] Z 12 Yes-OR 30 、-NR 31 R 32 、-C(O)NR 31 R 32 or -NR 33 C(O)R 34 ;

[0817] where R 30 is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclic group, -(CHR j ) o -(3-7C)cycloalkyl or -(CHR j ) o -[4-8 membered heterocyclyl], wherein R j is hydrogen or methyl, o is 0 or 1;

[0818] R 31 and R 32 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-linked 4-8 membered heterocyclic group, (CHR i ) p -(3-7C)cycloalkyl or -(CHR i ) p -[4-8 membered heterocyclyl], wherein R i is hydrogen or methyl, and p is 0 or 1

[0819] or R 31 and R 32 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0820] R 33 is hydrogen or methyl;

[0821] R 34 is (1-6C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclic group, -(CHR h ) q -(3-7C)cycloalkyl or -(CHR h ) q -[4-8 membered heterocyclyl], wherein R h is hydrogen or methyl, q is 0 or 1;

[0822] where R 30 、R 31 、R 32 or R34 , or when R 31 and R 32 Any ring formed when connected, optionally with one or more R a replace;

[0823] where R a As defined in any of paragraphs (106) to (114) above or below;

[0824] (104)R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or

[0825] R 14 Yes-(CHR k ) m -Z 14 ,

[0826] where R k is hydrogen;

[0827] wherein m is 0 or 1; and

[0828] Z 12 Yes-OR 30 、-NR 31 R 32 、-C(O)NR 31 R 32 or -NR 33 C(O)R 34 ;

[0829] where R 30 is (1-4C)alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR j ) o -[4-8 membered heterocyclyl], wherein R j is hydrogen or methyl, o is 0 or 1;

[0830] R 31 and R 32 Each is independently selected from hydrogen, (1-6C) alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR i ) p -[4- to 8-membered heterocyclyl], wherein R i is hydrogen or methyl, and p is 0 or 1

[0831] or R 31 and R 32 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring;

[0832] R33 It is hydrogen;

[0833] R 34 is (1-6C)alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR h ) q -[4-8 membered heterocyclic group],

[0834] where R h is hydrogen or methyl, q is 0 or 1;

[0835] where R 30 、R 31 、R 32 or R 34 , or when R 31 and R 32 Any ring formed when connected, optionally with one or more R a replace;

[0836] where R a As defined in any of paragraphs (106) to (114) above or below;

[0837] (105)R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups;

[0838] (106) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-4C)alkyl or a group

[0839] -L 1 -X 1 -Q 1

[0840] in:

[0841] L 1 Absent or (1-2C)alkylene;

[0842] X 1 Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)-、-NR 14 -、-SO2N(R 14 )-or-N(R 14 )SO2-, where R 14 is hydrogen or (1-2C)alkyl;

[0843] Q 1 selected from the group consisting of hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0844] (107) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0845] -L 1 -X 1 -Q 1

[0846] in:

[0847] L 1 Absent or (1-2C)alkylene;

[0848] X 1 Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)-、-NR 14 -、-SO2N(R 14 )-or-N(R 14 )SO2-, where R 14 is hydrogen or (1-2C)alkyl;

[0849] Q 1 selected from the group consisting of hydrogen, (1-2C)alkyl or (3-6C)cycloalkyl;

[0850] (108) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0851] -L 1 -X 1 -Q 1

[0852] in:

[0853] L 1 Absent or (1-2C)alkylene;

[0854] X 1 Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)- or -NR14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl;

[0855] Q 1 selected from the group consisting of hydrogen or (1-2C)alkyl;

[0856] (109) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0857] -L 1 -X 1 -Q 1

[0858] in:

[0859] L 1 does not exist;

[0860] X 1 Not present or selected from -O-, -C(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)- or -NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl;

[0861] Q 1 selected from the group consisting of hydrogen or (1-2C)alkyl;

[0862] (110) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0863] -L 1 -X 1 -Q 1

[0864] in:

[0865] L 1 does not exist;

[0866] X 1 Not present or selected from -O-, -C(O)-, -C(O)-N(R 14 )-or-NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl;

[0867] Q 1 selected from the group consisting of hydrogen or (1-2C)alkyl;

[0868] Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-4C)alkyl or a group

[0869] -L 1 -X 1 -Q 1

[0870] in:

[0871] L 1 Absent or (1-2C)alkylene;

[0872] X 1 Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)-、-NR 14 -、-SO2N(R 14 )-or-N(R 14 )SO2-, where R 14 is hydrogen or (1-2C)alkyl;

[0873] Q 1 selected from the group consisting of hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0874] When Q 1 When Q is (1-4C)alkyl or (3-6C)cycloalkyl, 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy;

[0875] (111) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0876] -L 1 -X 1 -Q 1

[0877] in:

[0878] L 1 Absent or (1-2C)alkylene;

[0879] X 1Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)-、-NR 14 -、-SO2N(R 14 )-or-N(R 14 )SO2-, where R 14 is hydrogen or (1-2C)alkyl;

[0880] Q 1 selected from the group consisting of hydrogen, (1-3C)alkyl, or (3-6C)cycloalkyl;

[0881] When Q 1 When Q is (1-3C)alkyl or (3-6C)cycloalkyl, 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy

[0882] (112) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0883] -L 1 -X 1 -Q 1

[0884] in:

[0885] L 1 Absent or (1-2C)alkylene;

[0886] X 1 Not present or selected from -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 - a group consisting of R 14 is hydrogen or (1-2C)alkyl;

[0887] Q 1 selected from the group consisting of hydrogen or (1-3C)alkyl;

[0888] Wherein when Q1 is (1-3C) alkyl, Q1 is optionally replaced by one or more Q a Substitute, where each Qa independently selected from the group consisting of (1-3C)alkoxy

[0889] (113) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0890] -L 1 -X 1 -Q 1

[0891] in:

[0892] L 1 does not exist;

[0893] X 1 Not present or selected from -O-, -C(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)- or -NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl;

[0894] Q 1 selected from the group consisting of hydrogen or (1-3C)alkyl;

[0895] When Q 1 When it is (1-3C) alkyl, Q 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of (1-2C)alkoxy

[0896] (114) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group

[0897] -L 1 -X 1 -Q 1

[0898] in:

[0899] L 1 does not exist;

[0900] X 1 Not present or selected from -O-, -C(O)-, -C(O)-N(R 14 )-or-NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl;

[0901] Q 1 selected from the group consisting of hydrogen or (1-3C)alkyl;

[0902] When Q 1 When it is (1-3C) alkyl, Q 1 By one or more Q a Substitute, where each Q a It's a methoxy group.

[0903] Probe compounds

[0904] (115) L is a (2-20C)alkylene linker, wherein the alkylene chain optionally further comprises one or more -O-, -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its ends, wherein R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0905] (116) L is a (3-20C)alkylene linker, wherein the alkylene chain optionally further comprises one or more -O-, -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its ends, wherein R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0906] (117) L is a (2-20C)alkylene linker, wherein the alkylene chain further comprises one to eight -O- bonds and / or one to four -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its ends;

[0907] where R 10is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0908] (118) L is a (3-20C)alkylene linker, wherein the alkylene chain further comprises one to eight -O- bonds and / or one to four -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its ends;

[0909] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0910] (119) L is a (2-18C)alkylene linker, wherein the alkylene chain optionally further comprises one to five -O- bonds; and / or one to four -C(O)-, -C(O)NR 10 -、-NR 10 a C(O)-, -C(O)O-, -OC(O)- bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one end thereof,

[0911] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0912] (120) L is a (3-12C)alkylene linker, wherein the alkylene chain optionally further comprises one to five -O- bonds; and / or one to four -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)- or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one end thereof,

[0913] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0914] (121) L is a (2-18C)alkylene linker, wherein the alkylene chain further comprises one to five -O- bonds and / or one to three -

[0915] C(O)-、-C(O)NR 10 -or-NR 10 a C(O)-bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini;

[0916] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0917] (122) L is a (3-12C)alkylene linker, wherein the alkylene chain further comprises one to five -O- bonds and / or one to three -C(O)-, -C(O)NR 10 -or-NR 10 a C(O)-bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini;

[0918] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0919] (123) L is a (2-18C)alkylene linker, wherein the alkylene chain further comprises one to five -O- bonds and / or one to three -C(O)-, -C(O)NR 10 -or-NR 10 C(O)-bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its ends, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0920] (124) L is a (3-12C)alkylene linker, wherein the alkylene chain further comprises one to five -O- bonds and / or one to three -C(O)-, -C(O)NR 10 -or-NR 10 C(O)-bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its ends, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0921] (125) L is a (2-18C)alkylene linker, wherein the alkylene chain further comprises one to three -O- bonds and / or one to three -C(O)-, -C(O)NR10- or -NR10C(O)- bonds or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0922] (126) L is a (3-12C)alkylene linker, wherein the alkylene chain further comprises one to three -O- bonds and / or one to three -C(O)-, -C(O)NR10- or -NR10C(O)- bonds or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0923] (127) L is a (2-18C)alkylene linker, wherein the alkylene chain further comprises an -O- bond and / or a -C(O)-, -C(O)NR10- or -NR10C(O)- bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0924] (128) L is a (3-12C)alkylene linker, wherein the alkylene chain further comprises an -O- bond and / or a -C(O)-, -C(O)NR10- or -NR10C(O)- bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0925] (129) L is a (2-17C)alkylene linker, wherein the alkylene chain optionally further comprises one to four -O- bonds and / or one to three -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its ends;

[0926] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0927] (130) L is a (3-10C)alkylene linker, wherein the alkylene chain optionally further comprises one to four -O- bonds and / or one to three -C(O)-, -C(O)NR10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its ends;

[0928] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0929] (131) L is a (2-17C)alkylene linker, wherein the alkylene chain further comprises one to four -O- bonds; and / or one to three -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its ends;

[0930] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0931] (132) L is a (3-10C)alkylene linker, wherein the alkylene chain further comprises one to four -O- bonds; and / or one to three -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its ends;

[0932] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0933] (133) L is a (2-17C)alkylene linker, wherein the alkylene chain further comprises one to four -O- bonds; and / or one to three -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its termini;

[0934] where R 10is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0935] (134) L is a (3-10C)alkylene linker, wherein the alkylene chain further comprises one to four -O- bonds; and / or one to three -C(O)-, -C(O)NR 10 -、-NR 10 C(O)-, piperazine or triazole ring bonds, which are located within the alkylene chain and / or at one of its termini;

[0936] where R 10 is hydrogen or (1-2C)alkyl, and wherein the alkylene chain is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, amino, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)haloalkyl or (1-2C)alkoxy.

[0937] (135) L is a (2-17C)alkylene linker, wherein the alkylene chain further comprises one to four -O- bonds and / or one to three -C(O)-, -C(O)NR 10 -or-NR 10 C(O)-bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its ends, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0938] (136) L is a (3-10C)alkylene linker, wherein the alkylene chain further comprises one to four -O- bonds and / or one to three -C(O)-, -C(O)NR 10 -or-NR 10 C(O)-bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its ends, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0939] (137) L is a (2-17C)alkylene linker, wherein the alkylene chain further comprises one to three -O- bonds and / or one to three -C(O)-, -C(O)NR10- or -NR10C(O)- bonds or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0940] (138) L is a (3-10C)alkylene linker, wherein the alkylene chain further comprises one to three -O- bonds and / or one to three -C(O)-, -C(O)NR10- or -NR10C(O)- bonds or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0941] (139) L is a (2-17C)alkylene linker, wherein the alkylene chain further comprises an -O- bond and / or a -C(O)-, -C(O)NR 10 -or-NR 10 C(O)-bond or a triazole ring bond, which is located within the alkylene chain and / or at one of its ends, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0942] (140) L is a (3-10C)alkylene linker, wherein the alkylene chain further comprises an -O- bond and / or a -C(O)-, -C(O)NR10- or -NR10C(O)- bond or a piperazine or triazole ring bond, which is located within the alkylene chain and / or at one of its termini, and wherein R 10 is hydrogen or (1-2C)alkyl.

[0943] (141) L is a linker having the formula:

[0944] -L p1 -X p1 -L p2 -X p2 -L p3 -

[0945] in

[0946] L p1 Absent or (1-8C)alkylene;

[0947] X p1 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)-, -C(O)O-, -OC(O)- or piperazine or triazole ring;

[0948] L p2 is (1-10C)alkylene or -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a -, wherein a is 1-10, and b is 2-4;

[0949] X p2 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)-, -C(O)O-, -OC(O)- or piperazine or triazole ring;

[0950] L p3 Absent or (1-8C)alkylene;

[0951] where R p1 is hydrogen or (1-2C)alkyl; and

[0952] The condition is X p1 or X p2 At least one of them exists;

[0953] (142) L is a linker having the formula:

[0954] -L p1 -X p1 -L p2 -X p2 -L p3 -

[0955] in

[0956] L p1 Absent or (1-6C)alkylene;

[0957] X p1 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)-, -C(O)O-, -OC(O)- or piperazine or triazole ring;

[0958] L p2 is (1-10C)alkylene or -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a -, wherein a is 2-10, and b is 2-4;

[0959] X p2 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)-, -C(O)O-, -OC(O)- or piperazine or triazole ring;

[0960] L p3 Absent or (1-6C)alkylene;

[0961] where Rp1 is hydrogen or methyl; and

[0962] The condition is X p1 or X p2 At least one of

[0963] (143) L is a linker having the formula:

[0964] -L p1 -X p1 -L p2 -X p2 -L p3 -

[0965] in

[0966] L p1 Absent or (2-6C)alkylene;

[0967] X p1 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)- or piperazine or triazole ring;

[0968] L p2 is (2-10C)alkylene or -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a -, wherein a is 2-10, and b is 2-4;

[0969] X p2 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)- or piperazine or triazole ring;

[0970] L p3 Absent or (1-6C)alkylene;

[0971] where R p1 is hydrogen or methyl; and

[0972] The condition is X p1 or X p2 At least one of them exists;

[0973] (144) L is a linker having the formula:

[0974] -L p1 -X p1 -L p2 -X p2 -Lp3 -

[0975] in

[0976] L p1 Absent or (2-6C)alkylene;

[0977] X p1 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)- or piperazine or triazole ring;

[0978] L p2 is (2-6C)alkylene or -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a -, wherein a is 2-10, and b is 2-4;

[0979] X p2 Not present or selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)- or piperazine or triazole ring;

[0980] L p3 Absent or (2-6C)alkylene;

[0981] where R p1 is hydrogen or methyl; and

[0982] The condition is X p1 or X p1 At least one of them exists;

[0983] (145) L is a linker having the formula:

[0984] -L p1 -X p1 -L p2 -X p2 -L p3 -

[0985] in

[0986] L p1 does not exist;

[0987] X p1 does not exist;

[0988] L p2 Absent or (2-6C)alkylene or -[CH2CH2-O] a -[CH2] b-or-[CH2] b -[O-CH2CH2] a -, wherein a is 2-10, and b is 2-4;

[0989] X p2 Selected from -O-, -C(O)-, -C(O)NR p1 -、-NR p1 C(O)- or triazole ring;

[0990] L p3 Absent or (2-6C)alkylene;

[0991] where R p1 is hydrogen or methyl; and

[0992] The condition is X p1 or X p2 At least one of them exists;

[0993] (146) L is a linker having the formula:

[0994] -L p1 -X p1 -L p2 -X p2 -L p3 -

[0995] in

[0996] L p1 is (2-6C)alkylene;

[0997] X p1 Selected from -O-, -C(O)NR p1 -、-NR p1 C(O)- or piperazine or triazole ring;

[0998] L p1 is (2-6C)alkylene or -[CH2CH2-O] a -[CH2] b -or-[CH2] b -[O-CH2CH2] a -group,

[0999] Where a is 2-10, and b is 2-4;

[1000] X p2 Selected from -O-, -C(O)NR p1 -、-NR p1 C(O)- or triazole ring;

[1001] L p3 is (2-6C)alkylene;

[1002] where R p1 is hydrogen or methyl; and

[1003] The condition is X p1 or X p2 At least one of them exists;

[1004] (147) Q is a detection moiety selected from the group consisting of a fluorophore, an oligonucleotide, a biomolecule, a molecular sensor, a protein, or a peptide;

[1005] (148) Q is a fluorophore;

[1006] (149) Q is a fluorophore selected from the group consisting of Alexa Fluor dyes, cyanine dyes, fluorescein, BODIPY or a BODIPY derivative (e.g., BODIPY TMR), TAMRA, Oregon Green dye, FITC, Ru(bpy)3, rhodamine dyes, acridine orange, and Texas Red;

[1007] (150) Q is a fluorophore selected from AlexaFluor-647, AlexaFluor-633, AlexaFluor-594, AlexaFluor-488, cyanine-5B, cyanine-3B, fluorescein, BODIPY or a BODIPY derivative (e.g., BODIPY TMR), TAMRA, Oregon Green 488, Oregon Green 514, FITC, Ru(bpy)3, rhodamine dye, acridine orange, and Texas Red;

[1008] (151) X is a functional group capable of reacting with a functional group present on the detection moiety, thereby covalently binding the detection moiety to the compound of formula (I);

[1009] (152) X is a functional group capable of reacting with a functional group present on a detection moiety, thereby covalently binding the detection moiety to the compound of formula (I), wherein the detection moiety is selected from the group consisting of a fluorophore, an oligonucleotide, a biomolecule, a molecular sensor, a protein, or a peptide;

[1010] (153) X is a functional group X that is capable of reacting with a functional group present on the fluorophore, thereby covalently binding the fluorophore to the compound of formula (I);

[1011] (154) X is a functional group capable of reacting with a functional group present on a fluorophore, thereby covalently binding the fluorophore to the compound of formula (I), and wherein the fluorophore is as defined in paragraph (149) or (150) above;

[1012] (155) X is selected from halogen, N3 or ethynyl functional groups;

[1013] (156)X is ethynyl or N3;

[1014] (157)L x is a linker group L as defined in any of paragraphs (115) to (146) above;

[1015] (158)L x is a (1-8C)alkylene linker, wherein the alkylene chain optionally further comprises one or more -O-, -C(O)NR located within the alkylene chain and / or at one of its termini 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O-) or triazole ring bond, wherein R 10 is hydrogen or (1-2C)alkyl;

[1016] (159)L x is a (1-8C)alkylene linker, wherein the alkylene chain optionally further comprises an -O-, -C(O)NR located within the alkylene chain and / or at one of its termini 10 -、-NR 10 C(O)-, -C(O)O-, -OC(O-) or triazole ring bond, wherein R 10 is hydrogen or (1-2C)alkyl;

[1017] (160)L x is a (1-5C)alkylene linker; or

[1018] (161)L x is a (1-3C)alkylene linker.

[1019] Suitably, R 2 As defined in numbered paragraph (1) or (2) above. Most suitably, R 2 As defined in numbered paragraph (1) above.

[1020] Suitably, R 4 As defined in any of the above numbered paragraphs (4) to (7). More suitably, R 4 As defined in any of the above numbered paragraphs (5) to (7). Most suitably, R 4 As defined in numbered paragraph (6) above.

[1021] Suitably, R 3 As defined in any of the above numbered paragraphs (10) to (14). More suitably, R 3 As defined in any of the above numbered paragraphs (12) to (14). Most suitably, R 3As defined in numbered paragraph (14) above.

[1022] Suitably, R 3 and R 4 As defined in any of the above numbered paragraphs (8) to (21). More suitably, R 3 and R 4 As defined in any of the above numbered paragraphs (12) to (21). Even more suitably, R 3 and R 4 As defined in any of the above numbered paragraphs (16) to (21). Still even more suitably, R 3 and R 4 As defined in any of the above numbered paragraphs (18) to (21). Most suitably, R 3 and R 4 As defined in numbered paragraph (21) above.

[1023] Suitably, R 5 As defined in any of the above numbered paragraphs (22) to (24). More suitably, R 5 As defined in either of numbered paragraphs (23) or (24) above. Most suitably, R 5 As defined in numbered paragraph (24) above.

[1024] Suitably, R 6 As defined in any of the above numbered paragraphs (28) to (36). More suitably, R 6 As defined in any of the above numbered paragraphs (32) to (36). Even more suitably, R 6 As defined in any of the above numbered paragraphs (34) to (36). Most suitably, R 6 As defined in numbered paragraph (36) above.

[1025] Suitably, Y1 is as defined in numbered paragraphs (37), (37a) or (38) above. Most suitably, Y1 is as defined in numbered paragraphs (37) above.

[1026] Suitably, Y2 is as defined in any of the above numbered paragraphs (39) to (44). More suitably, Y2 is as defined in any of the above numbered paragraphs (41) to (44). Even more suitably, Y2 is as defined in the above numbered paragraphs (42), (43) or (44). Most suitably, Y2 is as defined in the above numbered paragraph (43).

[1027] Suitably, Al is as defined in any one of numbered paragraphs (45) to (47) above. Most suitably, Al is as defined in numbered paragraph (47) above.

[1028] Suitably, A2 is as defined in any one of numbered paragraphs (48) to (51) above. Most suitably, A2 is as defined in numbered paragraph (48) above.

[1029] Suitably, A3 is as defined in any of the above numbered paragraphs (52) to (55). Most suitably, A3 is as defined in the above numbered paragraph (52).

[1030] Suitably, A4 is as defined in any of the above numbered paragraphs (56) to (59). Most suitably, A4 is as defined in the above numbered paragraph (58).

[1031] Suitably, A1, A2, A3 and A4 are as defined in any of the numbered paragraphs (60) to (67) above. More suitably, A1, A2, A3 and A4 are as defined in any of the numbered paragraphs (63) to (67) above. Even more suitably, A1, A2, A3 and A4 are as defined in any of the numbered paragraphs (64) to (67) above. Most suitably, A1, A2, A3 and A4 are as defined in the numbered paragraph (64) above.

[1032] Suitably, R 11 As defined in any of the above numbered paragraphs (74) to (86). More suitably, R 11 As defined in any of the above numbered paragraphs (80) to (86). Even more suitably, R 11 As defined in any of the above numbered paragraphs (84) to (86). Most suitably, R 11 As defined in numbered paragraph (85) or (86) above.

[1033] Suitably, R 12 As defined in any of the above numbered paragraphs (89) to (96). More suitably, R 12 As defined in any of the above numbered paragraphs (91) to (96). Most suitably, R 12 As defined in numbered paragraphs (94), (95) or (96) above.

[1034] Suitably, R 13 As defined in any of the above numbered paragraphs (98) to (101). More suitably, R 13 As defined in numbered paragraphs (99) to (101) above. Most suitably, R 13 As defined in numbered paragraph (101) above.

[1035] Suitably, R 14As defined in any of the above numbered paragraphs (102) to (105). More suitably, R 14 As defined in numbered paragraphs (103), (104) or (105) above. Most suitably, R 14 As defined in numbered paragraph (105) above.

[1036] Suitably, R a As defined in any of the above numbered paragraphs (106) to (114). More suitably, R a As defined in any of the above numbered paragraphs (109) to (114). Even more suitably, R a As defined in any of the above numbered paragraphs (111) to (114). Most suitably, Ra is as defined in the above numbered paragraphs (112), (113) or (114).

[1037] Suitably, L is as defined in any of the above numbered paragraphs (115) to (146). More suitably, L is as defined in any of the above numbered paragraphs (129) to (146). Even more suitably, L is as defined in any of the above numbered paragraphs (139) to (146). Most suitably, L is as defined in any of the above numbered paragraphs (144), (145) or (146).

[1038] Suitably, Q is as defined in any of the above numbered paragraphs (147) to (150). More suitably, Q is as defined in any of the above numbered paragraphs (148) to (150). Most suitably, Q is as defined in the above numbered paragraphs (149) or (150).

[1039] Suitably, X is as defined in any of the above numbered paragraphs (151) to (156). More suitably, X is as defined in any of the above numbered paragraphs (153) to (156). More suitably, X is as defined in any of the above numbered paragraphs (154) to (156). Most suitably, X is as defined in the above numbered paragraph (156).

[1040] Appropriately, L x As defined in any of the above numbered paragraphs (157) to (161). More suitably, L x As defined in any of the above numbered paragraphs (159) to (161). Most suitably, L x As defined in the above numbered paragraph (161).

[1041] In a specific group of compounds of the present invention, the compounds have structures according to sub-formulas (II) to (I-XLV) as shown herein, or pharmaceutically acceptable salts, hydrates and / or solvates thereof. It should be understood that in the following embodiments, R 2 、R 3 、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,L,L x The definitions of X, Q and any associated substituents only apply when present in subformulae (II) to (I-XLV).

[1042] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (8) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (60); R 11 As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1043] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (6) above; R 3 As defined in numbered paragraph (8) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1044] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (14) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11 As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1045] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 3 and R 4 As defined in paragraph (18) above; 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1046] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (8) above; R 5 As defined in numbered paragraph (23) above; R 6 As defined in the above numbered paragraph (34); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A2, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11 As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1047] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (8) above; R 5As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (43); A1, A2, A3 and A4 as defined in the above numbered paragraph (64); R 11 As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1048] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (8) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11 As defined in the above numbered paragraph (84); R 12 As defined in the above numbered paragraph (88); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1049] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (8) above; R5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11 As defined in the above numbered paragraph (86); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1050] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3 As defined in numbered paragraph (8) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11 As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (101); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (106); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1051] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (3) above; R 3As defined in numbered paragraph (8) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (61); R 11 As defined in the above numbered paragraph (68); R 12 As defined in the above numbered paragraph (87); R 13 As defined in the above numbered paragraph (97); R 14 As defined in numbered paragraph (102); R a As defined in numbered paragraph (113) above; L as defined in numbered paragraph (115) above; Q as defined in numbered paragraph (147) above; X as defined in numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1052] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (4) above; R 3 As defined in numbered paragraph (10) above; R 5 As defined in the above numbered paragraph (22); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (39); A1, A2, A3 and A4 as defined in the above numbered paragraph (63); R 11 As defined in the above numbered paragraph (74); R 12 As defined in the above numbered paragraph (89); R 13 As defined in the above numbered paragraph (98); R 14 As defined in the above numbered paragraph (102); R a As defined in the above numbered paragraph (109); L as defined in the above numbered paragraph (115); Q as defined in the above numbered paragraph (147); X as defined in the above numbered paragraph (151); and L x As defined in the above numbered paragraph (157).

[1053] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (5) above; R 3As defined in numbered paragraph (12) above; R 5 As defined in the above numbered paragraph (23); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (41); A1, A2, A3 and A4 as defined in the above numbered paragraph (64); R 11 As defined in the above numbered paragraph (80); R 12 As defined in the above numbered paragraph (92); R 13 As defined in the above numbered paragraph (99); R 14 As defined in the above numbered paragraph (103); R a As defined in the above numbered paragraph (111); L as defined in the above numbered paragraph (129); Q as defined in the above numbered paragraph (148); X as defined in the above numbered paragraph (153); and L x As defined in the above numbered paragraph (159).

[1054] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 4 As defined in paragraph (5) above; R 3 As defined in numbered paragraph (12) above; R 5 As defined in the above numbered paragraph (23); Y1 as defined in the above numbered paragraph (37); Y2 as defined in the above numbered paragraph (41); A1, A2, A3 and A4 as defined in the above numbered paragraph (64); R 11 As defined in the above numbered paragraph (84); R 12 As defined in the above numbered paragraph (94); R 13 As defined in the above numbered paragraph (101); R 14 As defined in the above numbered paragraph (105); R a As defined in the above numbered paragraph (112); L as defined in the above numbered paragraph (139); Q as defined in the above numbered paragraph (149); X as defined in the above numbered paragraph (156); and L x As defined in the above numbered paragraph (161).

[1055] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 3 and R 4As defined in paragraph (12) above; 5 As defined in numbered paragraph (22) above; R 6 As defined in the above numbered paragraph (25); Y1 and Y2 are as defined in the above numbered paragraph (42); A1, A2, A3 and A4 are as defined in any of the above numbered paragraphs (64 to (67); R 11 As defined in the above numbered paragraph (70); R 12 As defined in the above numbered paragraph (90); R 13 As defined in the above numbered paragraph (99); R 14 As defined in the above numbered paragraph (105); R a As defined in any of the above numbered paragraphs (112) to (114); L is as defined in the above numbered paragraph (139); Q is as defined in the above numbered paragraph (149); X is as defined in the above numbered paragraph (154); and L x As defined in the above numbered paragraph (161).

[1056] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 3 and R 4 As defined in paragraph (15) above; R 5 As defined in numbered paragraph (22) above; R 6 As defined in the above-numbered paragraph (29); Y1 and Y2 are as defined in the above-numbered paragraph (42); A1 is as defined in the above-numbered paragraph (45); A2 is as defined in the above-numbered paragraph (48); A3 is as defined in the above-numbered paragraph (52); A4 is CH; R 11 As defined in the above numbered paragraph (80); R 12 As defined in the above numbered paragraph (95); R 13 As defined in the above numbered paragraph (100); and R a As defined in any of the above numbered paragraphs (112) to (114).

[1057] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 3 and R 4 As defined in paragraph (15) above; R 5 As defined in numbered paragraph (22) above; R6 As defined in the above-numbered paragraph (36); Y1 and Y2 are as defined in the above-numbered paragraph (42); A1 is as defined in the above-numbered paragraph (45); A2 is as defined in the above-numbered paragraph (48); A3 is as defined in the above-numbered paragraph (52); A4 is CH; R 11 As defined in the above numbered paragraph (84); R 12 As defined in the above numbered paragraph (95); R 13 As defined in the above numbered paragraph (101); and R a As defined in any of the above numbered paragraphs (112) to (114).

[1058] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV) or pharmaceutically acceptable salts, hydrates and / or solvates thereof: R 2 As defined in numbered paragraph (1) above; R 3 and R 4 As defined in paragraph (15) above; R 5 As defined in numbered paragraph (22) above; R 6 As defined in the above-numbered paragraph (36); Y1 and Y2 are as defined in the above-numbered paragraph (42); A1 is as defined in the above-numbered paragraph (45); A2 is as defined in the above-numbered paragraph (48); A3 is as defined in the above-numbered paragraph (52); A4 is CH; R 11 As defined in the above numbered paragraph (86); R 12 As defined in the above numbered paragraph (95); R 13 As defined in the above numbered paragraph (101); R a As defined in any of the above numbered paragraphs (112) to (114).

[1059] In one aspect of the present invention, the compound of formula I or sub-formulas (II) to (I-XLV) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 、R 3 、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,L,L x , X, Q and any associated substituents are as defined above, provided that R 12 or R 13 One of them is not a group:

[1060] -LQ

[1061] or

[1062] -Lx -X

[1063] Where L is the linker;

[1064] L x It is a joint;

[1065] X is a functional group; and

[1066] Q is the detection part.

[1067] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 2 、R 3 、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,L,L x , X, Q and any associated substituents are as defined above, provided that R 12 or R 13 One of the groups is:

[1068] -LQ

[1069] or

[1070] -L x -X

[1071] Where L is the linker;

[1072] L x It is a joint;

[1073] X is a functional group; and

[1074] Q is the detection part.

[1075] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 2 、R 3 、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,L,L x , X, Q and any associated substituents are as defined above, provided that R 12 or R 13 One of the groups is:

[1076] -LQ

[1077] wherein L is a linker as defined in any of the above numbered paragraphs (139) to (148); and

[1078] Q is a detection moiety as defined in any of the above numbered paragraphs (151) to (156).

[1079] In embodiments of the compounds of Sub-Formulae (II) to (I-XLV), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, R 2 、R 3 、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,L,L x , X, Q and any associated substituents are as defined above, provided that R 12 or R 13 One of the groups is:

[1080] -LQ

[1081] wherein L is a linker as defined in any of the above numbered paragraphs (144), (145), or (146); and

[1082] Q is a detection moiety as defined in numbered paragraph (149) or (150) above.

[1083] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 2 As defined in paragraph (1) above.

[1084] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 4 As defined in numbered paragraph (5) above.

[1085] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 4 As defined in numbered paragraph (6) above.

[1086] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 4 As defined in numbered paragraph (7) above.

[1087] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3 As defined in numbered paragraph (12) above.

[1088] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3 As defined in numbered paragraph (13) above.

[1089] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3As defined in numbered paragraph (14) above.

[1090] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (18) above.

[1091] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (19) above.

[1092] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (20) above.

[1093] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (21) above.

[1094] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 5 As defined in numbered paragraph (23) above.

[1095] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 5 As defined in numbered paragraph (24) above.

[1096] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 6 As defined in numbered paragraph (34) above.

[1097] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 6 As defined in numbered paragraph (35) above.

[1098] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 6 As defined in numbered paragraph (36) above.

[1099] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, A1, A2, A3 and A4 are as defined in numbered paragraph (64) above.

[1100] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 11 As defined in numbered paragraph (84) above.

[1101] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 11 As defined in numbered paragraph (85) above.

[1102] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 11 As defined in numbered paragraph (86) above.

[1103] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 12 As defined in numbered paragraph (94) above.

[1104] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 12 As defined in numbered paragraph (95) above.

[1105] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 12 As defined in numbered paragraph (96) above.

[1106] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 13 As defined in numbered paragraph (99) above.

[1107] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 13 As defined in numbered paragraph (100) above.

[1108] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 13 As defined in numbered paragraph (101) above.

[1109] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 14 As defined in numbered paragraph (103) above.

[1110] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 14 As defined in numbered paragraph (104) above.

[1111] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R 14 As defined in numbered paragraph (105) above.

[1112] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R a As defined in numbered paragraph (112) above.

[1113] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R a As defined in numbered paragraph (113) above.

[1114] In a specific group of compounds of formula (I) or subformulae (II) to (I-XLV) as defined herein, R a As defined in numbered paragraph (114) above.

[1115] Specific compounds of the present invention include any compound exemplified in this application, or a pharmaceutically acceptable salt or solvate thereof, in particular any of the following compounds:

[1116] (S)-(2-(Benzyloxy)-6-hydroxy-4-methoxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1117] (R)-(2-(Benzyloxy)-6-hydroxy-4-methoxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1118] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1119] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1120] (S)-(4-(Difluoromethyl)-2-hydroxy-6-((3-methoxybenzyl)oxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1121] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((dimethylamino)methyl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1122] 1-(3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)azetidin-1-yl)ethan-1-one

[1123] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone

[1124] (4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone

[1125] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1126] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1127] (S)-(4-(Difluoromethyl)-2-hydroxy-6-((4-methoxybenzyl)oxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1128] (S)-(4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1129] (S)-(4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1130] (S)-(4-(Difluoromethyl)-2-hydroxy-6-((4-methoxybenzyl)oxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1131] (S)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one

[1132] (S)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one

[1133] (R)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one

[1134] (R)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one

[1135] 3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)dihydrofuran-2(3H)-one

[1136] 3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)dihydrofuran-2(3H)-one

[1137] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1138] (S)-(6-((1H-imidazol-1-yl)methyl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone

[1139] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1140] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((dimethylamino)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1141] (S)-(6-((1H-imidazol-1-yl)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone

[1142] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1143] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-5-yl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1144] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-4-yl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1145] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-5-yl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1146] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-4-yl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1147] 2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((2-methoxyethyl)amino)isoindolin-2-yl)methanone

[1148] 2-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)-N,N-dimethylacetamide

[1149] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

[1150] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-(dimethylamino)ethoxy)isoindolin-2-yl)methanone

[1151] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone

[1152] ((2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((1-methylazetidin-3-yl)amino)isoindolin-2-yl)methanone

[1153] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone

[1154] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1155] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1156] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((2-methoxyethyl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1157] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1158] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1159] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1160] (2-(Benzyloxy)-4-s(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1161] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1162] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1163] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpiperidin-4-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1164] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1165] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((4-methylpiperazin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1166] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((4-methylpiperazin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1167] (7-((1H-imidazol-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone

[1168] (6-((1H-imidazol-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone

[1169] (5-((1H-imidazol-1-yl)methyl)isoindolin-2-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone

[1170] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone

[1171] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2-((dimethylamino)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone

[1172] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(3-((dimethylamino)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone

[1173] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(isoindolin-2-yl)methanone

[1174] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpyrrolidin-3-yl)oxy)isoindolin-2-yl)methanone

[1175] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpyrrolidin-3-yl)oxy)isoindolin-2-yl)methanone

[1176] 2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylazetidin-3-yl)oxy)isoindolin-2-yl)methanone

[1177] (4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone

[1178] (2-(Cyclopropylmethoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone

[1179] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(pyridin-4-yloxy)isoindolin-2-yl)methanone

[1180] (2-(Cyclopropylmethoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone

[1181] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1182] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1183] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)yl)methanone

[1184] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)yl)methanone

[1185] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylazetidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1186] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1187] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1188] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylazetidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1189] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-morpholinoethoxy)isoindolin-2-yl)methanone

[1190] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-(4-methylpiperazin-1-yl)ethoxy)isoindolin-2-yl)methanone

[1191] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(cyclopentylamino)-6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1192] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1193] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(difluoromethyl)-6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1194] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1195] ((S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1196] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-methoxyethoxy)isoindolin-2-yl)methanone

[1197] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((tetrahydro-2H-pyran-4-yl)oxy)isoindolin-2-yl)methanone

[1198] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone

[1199] 2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1200] (S)-(2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1201] (R)-(2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1202] (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1203] (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1204] (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1205] (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1206] (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1207] (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)isoindolin-2-carbonyl)benzonitrile

[1208] 3-(Benzyloxy)-5-hydroxy-4-(4-(pyrimidin-5-ylamino)isoindoline-2-carbonyl)benzonitrile

[1209] (R)-4-(4-((1-acetylpyrrolidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile

[1210] (S)-4-(4-((1-acetylpyrrolidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile

[1211] (R)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile or (S)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1212] 3-(Benzyloxy)-5-hydroxy-4-(4-((oxazol-4-ylmethyl)amino)isoindoline-2-carbonyl)benzonitrile

[1213] 3-(Benzyloxy)-5-hydroxy-4-(4-(((tetrahydrofuran-3-yl)methyl)amino)isoindoline-2-carbonyl)benzonitrile

[1214] 3-(Benzyloxy)-5-hydroxy-4-(4-methoxyisoindoline-2-carbonyl)benzonitrile

[1215] (R)-3-(Benzyloxy)-5-hydroxy-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzonitrile

[1216] (R)-3-(Benzyloxy)-5-hydroxy-4-(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1217] (S)-3-(Benzyloxy)-5-hydroxy-4-(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1218] 3-(Benzyloxy)-4-(5-((dimethylamino)methyl)isoindoline-2-carbonyl)-5-hydroxybenzonitrile

[1219] 4-(4-((1-acetylpiperidin-4-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile

[1220] (R)-4-(4-((1-acetylpiperidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile

[1221] (S)-4-(4-((1-acetylpiperidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile

[1222] 3-(Benzyloxy)-5-hydroxy-4-(4-((5-oxotetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1223] (2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(4-((1-methylazetidin-3-yl)amino)isoindolin-2-yl)methanone

[1224] 2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(2-((dimethylamino)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone

[1225] (2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1226] 1-(3-((2-(2-(Benzyloxy)-4-fluoro-6-hydroxybenzoyl)isoindolin-4-yl)amino)azetidin-1-yl)ethan-1-one

[1227] (2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1228] (2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone

[1229] 3-(Benzyloxy)-5-hydroxy-4-(4-(oxetan-3-ylamino)isoindoline-2-carbonyl)benzonitrile

[1230] (S)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-2-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1231] (R)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-2-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1232] 3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxybenzonitrile

[1233] (R)-3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylpyrrolidin-3-yl)oxy)isoindoline-2-carbonyl)benzonitrile

[1234] (S)-3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylpyrrolidin-3-yl)oxy)isoindoline-2-carbonyl)benzonitrile

[1235] 3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylazetidin-3-yl)oxy)isoindoline-2-carbonyl)benzonitrile

[1236] 3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylpiperidin-4-yl)oxy)isoindoline-2-carbonyl)benzonitrile

[1237] 3-(Benzyloxy)-5-hydroxy-4-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)benzonitrile

[1238] 3-(Benzyloxy)-5-hydroxy-4-(5-(2-methoxyethoxy)isoindoline-2-carbonyl)benzonitrile

[1239] 3-(Benzyloxy)-5-hydroxy-4-(5-((tetrahydro-2H-pyran-4-yl)oxy)isoindoline-2-carbonyl)benzonitrile

[1240] 3-Hydroxy-4-(5-((1-methylazetidin-3-yl)oxy)isoindoline-2-carbonyl)-5-(pyridin-2-ylmethoxy)benzonitrile

[1241] 3-Hydroxy-4-(4-(oxetan-3-ylamino)isoindoline-2-carbonyl)-5-(pyridin-2-ylmethoxy)benzonitrile

[1242] (S)-3-Hydroxy-5-(pyridin-2-ylmethoxy)-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1243] (S)-3-(Benzyloxy)-5-hydroxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1244] (S)-3-Hydroxy-5-methoxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1245] (S)-3-(Cyclopropylmethoxy)-5-hydroxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1246] (R)-3-(Benzyloxy)-5-hydroxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile

[1247] 3-(Benzyloxy)-5-hydroxy-4-(isoindoline-2-carbonyl)benzonitrile

[1248] 3-(Benzyloxy)-5-hydroxy-4-(5-methoxyisoindoline-2-carbonyl)benzonitrile

[1249] (R)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxybenzonitrile

[1250] (S)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxybenzonitrile

[1251] 4-(4-((1-acetazetidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile (S)-3-(benzyloxy)-5-hydroxy-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzonitrile

[1252] (R)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)-5-hydroxybenzonitrile

[1253] (S)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)-5-hydroxybenzonitrile

[1254] (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1255] (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1256] (S)-(2-(Benzyloxy)-6-hydroxy-4-(trifluoromethyl)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone

[1257] (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1258] (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1259] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(piperidin-4-yloxy)isoindolin-2-yl)methanone

[1260] 3-(Benzyloxy)-4-(6-((dimethylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)-5-hydroxybenzonitrile

[1261] 3-(Benzyloxy)-5-hydroxy-4-(6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)benzonitrile

[1262] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone

[1263] (S or R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone

[1264] 3-(Benzyloxy)-5-hydroxy-4-(6-((tetrahydrofuran-3-yl)amino)indoline-1-carbonyl)benzonitrile

[1265] 3-(Benzyloxy)-5-hydroxy-4-(5-((tetrahydrofuran-3-yl)amino)indoline-1-carbonyl)benzonitrile

[1266] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone

[1267] (S or R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone

[1268] 3-(Benzyloxy)-5-hydroxy-4-(7-((1-methylpiperidin-4-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-3-carbonyl)benzonitrile hydroformate

[1269] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpiperidin-4-yl)oxy)-1,2,4,5-tetrahydro-3H-benzo[d]azepan-3-yl)methanone

[1270] 3-(Benzyloxy)-5-hydroxy-4-(6-morpholino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)benzonitrile

[1271] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-morpholino-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone

[1272] 4-(6-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile hydroformate

[1273] (6-Amino-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone hydroformate

[1274] 3-(Benzyloxy)-4-(4-(2-(dimethylamino)ethoxy)indoline-1-carbonyl)-5-hydroxybenzonitrile

[1275] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-(2-(dimethylamino)ethoxy)indolin-1-yl)methanone

[1276] 3-(Benzyloxy)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-5-hydroxybenzonitrile

[1277] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methanone

[1278] 3-(Benzyloxy)-4-(2-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-5-hydroxybenzonitrile

[1279] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone

[1280] 3-(Benzyloxy)-5-hydroxy-4-(6-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroquinoline-1-carbonyl)benzonitrile

[1281] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((tetrahydrofuran-3-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)methanone

[1282] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)-4-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone

[1283] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone

[1284] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methanone

[1285] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone

[1286] (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone

[1287] (S)-(4-(Difluoromethyl)-2-hydroxy-6-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1288] (S)-(2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1289] (S)-(4-(Difluoromethyl)-2-hydroxy-6-(isoquinolin-6-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1290] (S)-(4-(Difluoromethyl)-2-hydroxy-6-(isoquinolin-7-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1291] (S)-(2-((1H-benzo[d]imidazol-2-yl)methoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[1292] The various functional groups and substituents comprising the compounds of formula (I) or subformulas (II) to (I-XLV) are typically selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and for example, is 550 or less.

[1293] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention having sufficient basicity, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, such as sodium salts or potassium salts, alkaline earth metal salts, such as calcium salts or magnesium salts, ammonium salts or salts formed with organic bases that provide pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholino or tris-(2-hydroxyethyl)amine.

[1294] Compounds with the same molecular formula but different bonding properties or order of their atoms or the arrangement of atoms in space are referred to as "isomers". Isomers with different spatial atomic arrangements are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", while those that are non-overlapping mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, there may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequential rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or with their mixtures. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[1295] The compounds of the present invention may have one or more asymmetric centers; thus, 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 the specification and claims is intended to include its individual enantiomers and mixtures, racemic or other forms thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some compounds of the present invention may have geometric isomeric centers (E and Z isomers).

[1296] It should be understood that the present invention includes all active optical isomers, diastereomers and geometric isomers and mixtures thereof.

[1297] The present invention also includes compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T); C can be in any isotopic form, including 12C, 13C, and 14C; and O can be in any isotopic form, including 16O and 18O; etc.

[1298] It will also be appreciated that certain compounds of formula (I) or sub-formulas (II) to (I-XLV) may exist in solvated and unsolvated forms, such as hydrated forms. It will be appreciated that the present invention encompasses all such active solvated forms.

[1299] It will also be appreciated that certain compounds of formula (I) or sub-formulas (II) to (I-XLV) may exhibit polymorphism and that the present invention encompasses all such active forms.

[1300] Compounds of formula (I) or subformula (II) to (I-XLV) can exist in many different tautomeric forms, and all of these forms are included when referring to compounds of formula (I) or subformula (II) to (I-XLV). For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are included in formula (I) or subformula (II) to (I-XLV). Examples of tautomeric forms include keto-, enol- and enolate-forms, such as the following tautomer pairs: keto / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol and nitro / acidic nitro.

[1301]

[1302] Compounds of formula (I) or sub-formulas (II) to (I-XLV) containing amine functional groups can also form N-oxides. The compounds of formula (I) or sub-formulas (II) to (I-XLV) containing amine functional groups mentioned herein also include N-oxides. When the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March's Advanced Organic Chemistry, 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA) in, for example, an inert solvent such as dichloromethane.

[1303] The compounds of formula (I) or subformulas (II) to (I-XLV) can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present invention. When the compounds of the present invention contain a suitable group or substituent, a prodrug can be formed to which the modifying group can be attached. Examples of prodrugs include ester derivatives that can be formed in vivo at the carboxyl or hydroxyl groups of the compounds of formula (I) or subformulas (II) to (I-XLV), and amide derivatives that can be formed in vivo at the carboxyl or amino groups of the compounds of formula (I) or subformulas (II) to (I-XLV).

[1304] Thus, the present invention includes those compounds of formula (I) or subformulas (II) to (I-XLV) as defined above, when obtained by organic synthesis, as well as when obtained in the human or animal body by cleavage of their prodrugs. Thus, the present invention includes those compounds of formula (I) or subformulas (II) to (I-XLV) produced by organic synthesis methods, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, i.e. compounds of formula (I) or subformulas (II) to (I-XLV), which may be synthetically produced compounds or metabolically produced compounds.

[1305] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or subformulas (II) to (I-XLV) are drugs that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity.

[1306] Various forms of prodrugs have been described, for example in the following documents:

[1307] a) Methods in Enzymology, Vol. 42, p. 309 - 396, edited by K. Widder, et al. (Academic Press, 1985);

[1308] b) Design of Pro - drugs, edited by H. Bundgaard, (Elsevier, 1985);

[1309] c) A Textbook of Drug Design and Development, edited by Krogsgaard - Larsen and

[1310] H. Bundgaard, Chapter 5 “Design and Application of Pro - drugs”, by H. Bundgaard p. 113 - 191 (1991);

[1311] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1 - 38 (1992);

[1312] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[1313] f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

[1314] g) T. Higuchi and V. Stella, “Pro - Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

[1315] h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1316] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or subformulas (II) to (I-XLV) having a carboxyl group are, for example, esters thereof which are cleavable in vivo. An in vivo cleavable ester of a compound of formula (I) or subformulas (II) to (I-XLV) containing a carboxyl group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or parent alcohol. Suitable pharmaceutically acceptable esters for the carboxyl group include (1-6C)alkyl esters such as methyl, ethyl and tert-butyl esters, (1-6C)alkoxymethyl esters such as methoxymethyl ester, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthaloyl ester, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxymethyl esters such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

[1317] The suitable pharmaceutically acceptable prodrug of formula (I) or subformula (II) to (I-XLV) compound with hydroxyl is for example its ester or ether that can be decomposed in vivo. The ester or ether that can be decomposed in vivo of formula (I) or subformula (II) to (I-XLV) compound containing hydroxyl is for example pharmaceutically acceptable ester or ether, and its cracking produces parent hydroxy compound in human body or animal body. The suitable pharmaceutically acceptable ester group of hydroxyl comprises inorganic ester, such as phosphate (comprising phosphoramide cyclic ester). Other suitable pharmaceutically acceptable ester groups of hydroxyl comprise (1-10C) alkanoyl, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-10C) alkoxycarbonyl, such as ethoxycarbonyl, N, N-(1-6C) 2 carbonyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl 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.

[1318] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or subformulas (II) to (I-XLV) having a carboxyl group are, for example, their in vivo cleavable amides, for example with amines such as ammonia, 1-4C alkylamines such as methylamine, [(1-4C) alkyl]2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, (1-4C) alkoxy-(2-4C) alkylamines such as 2-methoxyethylamine, phenyl-(1-4C) alkylamines such as benzylamine and amino acids such as glycine or their esters.

[1319] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or subformula (II) to (I-XLV) with amino are, for example, amide derivatives cleavable in vivo thereof. Suitable pharmaceutically acceptable amides from amino include, for example, amides formed by (1-10C) alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. The example of the ring substituent on phenylacetyl and benzoyl includes aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinemethyl, piperazine-1-ylmethyl and 4-(1-4C) alkyl)piperazine-1-ylmethyl.

[1320] The in vivo effects of the compounds of formula (I) or subformulas (II) to (I-XLV) may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compounds of formula (I) or subformulas (II) to (I-XLV). As mentioned above, the in vivo effects of the compounds of formula (I) or subformulas (II) to (I-XLV) may also be exerted by the metabolism of precursor compounds (prodrugs).

[1321] Although the present invention may relate to any compound or specific group of compounds defined herein by way of an optional, preferred or suitable feature or in the form of a specific embodiment, the present invention may also relate to any compound or specific group of compounds that specifically excludes that optional, preferred or suitable feature or specific embodiment.

[1322] Suitably, the present invention excludes any individual compound which does not possess the biological activity defined herein.

[1323] synthesis

[1324] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[1325] In the descriptions of synthetic methods described herein, and in any referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, duration of experiments, and work-up procedures, can be selected by one skilled in the art.

[1326] Those skilled in the art of organic synthesis will appreciate that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[1327] It will be appreciated that during the synthesis of the compounds of the invention in the methods defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undesirable reactions. A skilled chemist will understand when such protection is necessary and how to place such protecting groups in place and then remove them.

[1328] For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green's Protective Groups in Organic Synthesis (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist to be suitable for removing the protecting group in question, the method being selected so as to effect removal of the protecting group with minimal interference with other groups in the molecule.

[1329] Thus, if reactants include groups such as amino, carboxyl or hydroxy, it may be necessary to protect this group in some of the reactions mentioned herein.

[1330] For example, the suitable protecting group of amino or alkylamino is acyl group for example, and for example alkanoyl is such as acetyl, alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, arylmethoxycarbonyl, for example benzyloxycarbonyl, or aroyl, for example benzoyl.The deprotection condition of above-mentioned protecting group must change along with the selection of protecting group.Therefore, for example, acyl group such as alkanoyl or alkoxycarbonyl or aroyl can be removed by for example using suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide hydrolysis.Or, acyl group such as tert-butyloxycarbonyl can be removed by for example processing with suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl such as benzyloxycarbonyl can be for example by hydrogenation on catalyzer such as carbon-supported palladium, or by processing with Lewis acid such as three (trifluoroacetic acid boron) and remove.The suitable alternative protecting group of primary amino is phthaloyl for example, and it can be by using alkylamine, for example dimethylaminopropylamine, or removes with hydrazine processing.

[1331] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, for example, alkanoyl groups such as acetyl groups, aroyl groups such as benzoyl groups, or arylmethyl groups such as benzyl groups. The deprotection conditions for the above-mentioned protecting groups will inevitably vary with the selection of the protecting group. Therefore, for example, acyl groups such as alkanoyl groups or aroyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon.

[1332] A suitable protecting group for a carboxyl group is, for example, an esterifying group, such as a methyl or ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or a tert-butyl group which can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid, or a benzyl group which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[1333] The resin can also serve as a protecting group.

[1334] The method used to synthesize the compounds of formula (I) or sub-formulae (II) to (I-XLV) will vary depending on the nature of any substituents or subunits associated therewith. Suitable methods for their preparation are further described in the accompanying Examples.

[1335] Once a compound of formula (I) or sub-formulas (II) to (I-XLV) has been synthesized by any of the methods defined herein, the method may further comprise the additional step of:

[1336] (i) removing any protecting groups present;

[1337] (ii) converting a compound of formula (I) into another compound of formula (I);

[1338] (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or

[1339] (iv) forming a prodrug thereof.

[1340] An example of the above (ii) is when synthesizing a compound of formula (I), then one or more groups R 2 、R 3 、R 4 、R 5 、R 11 、R 12 、R 13 or R 14 Further reactions may be carried out to modify the nature of this group and provide alternative compounds of formula (I).

[1341] The resulting compounds of formula (I) or sub-formulae (II) to (I-XLV) can be isolated and purified using techniques well known in the art.

[1342] The compounds of formula (I) can be synthesized by the synthetic routes shown in the Examples section below.

[1343] Biological activity

[1344] The bioassays described in the Examples section herein can be used to measure the pharmacological effects of the compounds of the invention.

[1345] Although the pharmacological properties of the compounds of formula (I) vary with structure, the compounds of the invention were found to be active in the MLH1 in vitro assay described in the Examples section.

[1346] Pharmaceutical composition

[1347] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[1348] The compositions of the present 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), in a form suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[1349] The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral administration may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[1350] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with a proliferative condition as referred to herein.

[1351] 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 being treated and the particular route of administration. For example, a formulation for oral administration to humans typically contains, for example, 0.5 mg to 0.5 g of active agent (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg), mixed with an appropriate and convenient amount of excipients, which may comprise from about 5% to about 98% by weight of the total composition.

[1352] According to well-known medical principles, the size of the dose of the compound of formula I for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[1353] When the compound of the present invention is used for treatment or prevention purposes, the compound is usually applied, so as to obtain a daily dose (if necessary with divided doses) within the range of, for example, 0.1mg / kg to 75mg / kg body weight. In general, when parenteral route is adopted, a lower dosage will be applied. Therefore, for example, for intravenous or intraperitoneal administration, a dosage within the range of 0.1mg / kg to 30mg / kg body weight will be usually used. Similarly, for inhalation administration, a dosage within the range of, for example, 0.05mg / kg to 25mg / kg body weight will be used. Oral administration is also suitable, especially in tablet form. Typically, a unit dosage form will contain a compound of the present invention of about 0.5mg to 0.5g.

[1354] Therapeutic uses and applications

[1355] The present invention provides compounds that are useful as inhibitors of MLH1 activity.

[1356] Therefore, the compounds of formula (I) or pharmaceutically acceptable salts thereof have potential therapeutic uses in a variety of disease states where inhibition of MLH1 activity is beneficial.

[1357] The present invention thus provides a method of treating a disease or condition in which inhibition of MLH1 activity is beneficial to a patient in need of such treatment, said method comprising 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 thereof.

[1358] The present invention provides a method for inhibiting MLH1 activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1359] The present invention provides a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1360] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1361] 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.

[1362] 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.

[1363] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disease.

[1364] 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 treating cancer. In particular embodiments, the cancer is a human cancer. In a specific embodiment, the cancer is a human cancer, particularly an estrogen-positive cancer, such as breast cancer, or an androgen receptor-positive cancer, such as prostate cancer.

[1365] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting MLH1 activity.

[1366] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating a disease or condition in which inhibition of MLH1 activity is beneficial.

[1367] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for the treatment of a proliferative disease.

[1368] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for the treatment of cancer.

[1369] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for inhibiting MLH1 activity.

[1370] 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 a disease or condition in which inhibition of MLH1 activity is beneficial.

[1371] The terms "proliferative disorder," "proliferative condition," and "proliferative disease" are used interchangeably herein and relate to the unwanted or uncontrolled cellular proliferation of unwanted excess or abnormal cells, such as a tumor or hyperplastic growth, whether in vitro or in vivo.

[1372] In the above aspects of the invention, the proliferative disease is suitably cancer, and the cancer is suitably a human cancer. In the aspects of the invention outlined herein, the proliferative disease is suitably cancer, and the cancer is suitably a human cancer. In particular, the compounds of the invention will be useful in treating any cancer in which mismatch repair inhibition and / or cGAS / STING pathway activation is beneficial.Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal tumors, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, biliary tract cancer (bile duct cancer), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney syndrome, central nervous system tumor, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer) , eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor-GIST, germ cell 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 cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemias (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B cell Prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal and sinus cancer, pharyngeal cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis type 1 and type 2, nevoid basal cell carcinoma syndrome, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas (e.g., Kaposi sarcoma or soft tissue), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic cancer, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom macroglobulinemia, Werner syndrome, Wilms tumor, and xeroderma pigmentosum).Particular cancers of interest include hematological cancers, such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastroesophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, bile duct cancer, central nervous system cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[1373] The compounds of the present invention are also useful in the treatment of triplet disorders.

[1374] Thus, another aspect of the present invention provides a method of treating a triad disorder (e.g., Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA) and spinocerebellar ataxia (SCA)) in a patient in need of such treatment, said method comprising 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.

[1375] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in the treatment of a triplet disorder. In a specific embodiment, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA) and spinocerebellar ataxia (SCA).

[1376] According to another 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 preparation of a medicament for treating a triplet disorder. In a specific embodiment, the triplet disorder is selected from the group consisting of Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA) and spinocerebellar ataxia (SCA).

[1377] Route of administration

[1378] The compounds of the invention, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the site of desired action).

[1379] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patch, plaster, etc.); transmucosal (including, for example, by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., through the mouth or nose, using, for example, an aerosol); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, e.g., by injection, including intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or depot, e.g., subcutaneously or intramuscularly.

[1380] Combination therapy

[1381] The compounds of the present invention may be administered as a monotherapy or, in addition to the compounds of the present invention, may also include conventional surgery or radiotherapy or chemotherapy or targeted agents. Such chemotherapy or targeted agents may include one or more of the following categories:

[1382] (i) antiproliferative / antineoplastic drugs and combinations thereof for use in medical oncology, such as, but not limited to, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, butylsulfonyl, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines, such as doxorubicin); n), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and docetaxel, and multikinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

[1383] (ii) cytostatic agents, such as, but not limited to, antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodofenoxetine), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), steroid hormones, including progestins (e.g., megestrol acetate) and corticosteroids (e.g., dexamethasone, prednisone, and prednisolone), aromatase inhibitors (e.g., anastrozole, letrozole, forazol, and exemestane), and 5-reductase inhibitors, such as finasteride;

[1384] (iii) anti-invasive agents, such as, but not limited to, the c-Src kinase family inhibitors 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47 ,6658-6661), bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors, or heparanase antibodies;

[1385] (iv) inhibitors of growth factor function, such as, but not limited to, growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib (BAY 43-9006), tipifarnib (R115777), and lonafarnib (SCH66336)), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[1386] (v) anti-angiogenic agents, such as, but not limited to, those that inhibit the action of vascular endothelial growth factor (VEGF), [e.g., the anti-VEGF antibody bevacizumab (Avastin TM ) and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736) and pazopanib (GW 786034).

[1387] (vi) vascular damaging agents, such as, but not limited to, Compretin A4 and the compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[1388] (vii) endothelin receptor antagonists, such as zilpotan (ZD4054) or atrasentan;

[1389] (viii) antisense therapies, such as, but not limited to, those directed against the targets listed above, e.g., ISIS2503, an anti-ras antisense;

[1390] (ix) Immunotherapy, including, for example, cancer vaccines, antibodies, viruses (oncolytic viruses), and small molecules or cell therapies to increase the immunogenicity of patient tumor cells and / or promote cell-mediated anti-tumor responses. Such therapies may include, but are not limited to, OX40 agonists, cGAS-STING agonists, A2a receptor antagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, arginase inhibitors, BTK inhibitors, and bromodomain inhibitors; transduction with microbial vectors of cancer antigens, direct transduction of cancer antigens into antigen-presenting cells, treatment with immune cells specific for cancer antigens (e.g., CAR-T), and treatment with antibodies, antibody fragments, and antibody-drug conjugates that enable the immune system to recognize tumor cells.

[1391] Such combination treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[1392] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (eg cancer involving solid tumours) comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt or solvate thereof, and an anti-tumour agent.

[1393] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative disease such as cancer (e.g. a cancer involving solid tumours) comprising a compound of the invention as defined above or a pharmaceutically acceptable salt or solvate thereof, and any one of the anti-tumour agents listed above.

[1394] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in treating cancer in combination with another anti-tumor agent, optionally selected from one of the above-listed agents.

[1395] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in treating cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed above.

[1396] As used herein, the term "combination" is understood to refer to simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. When administered sequentially or separately, a delayed administration of the second component should not result in a loss of the beneficial effects of the combination.

[1397] According to another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, in combination with an anti-tumor agent (optionally selected from the one listed above) and a pharmaceutically acceptable diluent or carrier.

[1398] Combination therapy with immunomodulatory therapy

[1399] Immune checkpoint inhibitors

[1400] Immune checkpoint proteins present on immune cells and / or cancer cells [such as CTLA4 (also known as cytotoxic T lymphocyte-associated protein 4 and CD152), LAG3 (also known as lymphocyte activation gene 3 and CD223), PD1 (also known as programmed cell death protein 1 and CD279), PD-L1 (also known as programmed death ligand 1 and CD274), TIM-3 (also known as T cell immunoglobulin mucin-3), and TIGIT (also known as T cell immunoreceptor with Ig and ITIM domains) are molecular targets that have been found to play an important role in regulating anti-tumor immune responses. Inhibitors of these immune checkpoint proteins (such as CTLA4, LAG3, PD1, PD-L1, TIM-3, and / or TIGIT inhibitors) promote anti-tumor immune responses and can be used to effectively treat certain forms of cancer.

[1401] Immunostimulants

[1402] Monoclonal antibodies, bispecific antibodies, recombinant ligands and small molecule therapeutics that bind to stimulatory receptors on immune cells can promote effective anti-tumor responses. Such receptors may be involved in cell-to-cell contact, such as contact between tumor cells and immune cells or between two types of immune cells, and other receptors may bind to soluble factors that stimulate immune responses. In one such embodiment, antibodies, bispecifics, recombinant proteins or small molecule therapeutics can activate stimulatory receptors, including but not limited to 4-1BB, OX40, cGAS-STING, CD27, CD40 and DR3, which enhance anti-tumor immunity.

[1403] Modulators of antigen processing can promote the presentation of neoantigenic peptides on the cell surface, thereby enhancing effective anti-tumor responses. In one such embodiment, inhibitors of the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 can stimulate anti-tumor immunity.

[1404] 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 immunostimulatory agent as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease.

[1405] In another aspect, the present invention relates to the use of a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulatory agent as defined herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a proliferative disease.

[1406] In another aspect, the present invention relates to a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulatory agent as defined herein, or a pharmaceutically acceptable salt thereof.

[1407] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with an immune checkpoint inhibitor or an immunostimulatory agent, or a pharmaceutically acceptable salt thereof.

[1408] In another aspect, the present invention relates to an immune checkpoint inhibitor or an immunostimulatory agent or a pharmaceutically acceptable salt thereof for use in treating a proliferative disease, wherein the immune checkpoint inhibitor is for simultaneous, separate or sequential administration with a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1409] In another aspect, the present invention relates to the use of a compound as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a proliferative disease, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor or an immunostimulatory agent or a pharmaceutically acceptable salt thereof.

[1410] In another aspect, the present invention relates to the use of an immune checkpoint inhibitor or an immunostimulatory agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a proliferative disease, wherein the medicament is for simultaneous, separate or sequential administration with a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1411] In another aspect, the present invention relates to a method for treating a proliferative disease, which method comprises sequentially, separately or simultaneously administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor or immunostimulatory agent as defined herein or a pharmaceutically acceptable salt thereof.

[1412] Any immune checkpoint inhibitor or immunostimulatory agent may be used in the combination therapy defined herein.

[1413] In one embodiment, the immunostimulant is selected from 4-1BB stimulants, OX40 stimulants, CD27 stimulants, CD40 stimulants and DR3 stimulants. In another embodiment, the immune checkpoint inhibitor is selected from PD1 inhibitors, PD-L1 inhibitors, LAG3 inhibitors, CTLA-4 inhibitors, TIM-3 inhibitors and / or TIGIT inhibitors. In a specific embodiment, the immune checkpoint inhibitor is PD1 or PD-L1 inhibitor.

[1414] PD-1 is a cell surface receptor protein present on immune cells such as T cells. PD-1 plays an important role in downregulating the immune system and promoting self-tolerance by inhibiting T cell activation. The PD-1 protein is an immune checkpoint that prevents autoimmunity through a dual mechanism: promoting apoptosis (programmed cell death) of antigen-specific T cells in the lymph nodes while simultaneously reducing apoptosis of regulatory T cells (anti-inflammatory suppressor T cells).

[1415] PD-1 thus suppresses the immune system. This can prevent autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

[1416] PD-1 binds to two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest because it is highly expressed in several cancers, and thus the role of PD-1 in cancer immune evasion is well established. Monoclonal antibodies targeting the immune-stimulating PD-1 have been approved or are in development for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive ligand of PD-1; inhibiting the interaction between PD-1 and PD-L1 can enhance T cell responses in vitro and mediate preclinical anti-tumor activity. This is known as immune checkpoint blockade.

[1417] Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma. They are also being studied against many other types of cancer. Drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics), and MEDI-0680 (MedImmune).

[1418] Drugs that inhibit 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 the treatment of other types of cancer.

[1419] Examples of LAG3 inhibitors include BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds PD-1 and LAG-3), GSK2831781, and LAG525.

[1420] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN 1884, and CP-675,206 / tremelimumab.

[1421] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Eli Lilly).

[1422] Examples of TIGIT inhibitors include tisleliumab (MTIG7192A; RG6058; Genentech / Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207 (Bristol-Myers Squibb), and ASP8374 (Astellas Pharma; Potenza Therapeutics).

[1423] In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / Ipilimumab, AGEN1884 and CP-675, 206 / Tremelimumab, Pembrolizumab, Nivolumab, Atezolizumab, Avelumab, Durvalumab, MBG453, TSR-022, LY3321367, Tirelizumab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207 and / or ASP8374, or a pharmaceutically acceptable salt or solvate thereof.

[1424] Combination therapy with DNA damage response modulators

[1425] The compounds of the present invention are particularly suitable for use in combination with drugs that act as modulators of the DNA damage response, such as PARP inhibitors, ATM inhibitors and ATR inhibitors.

[1426] In one aspect, the invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease.

[1427] In another aspect, the present invention relates to the use of a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a proliferative disease.

[1428] In another aspect, the present invention relates to a method of treating a proliferative disease in a subject in need thereof, which method comprises administering to the 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) as defined herein, or a pharmaceutically acceptable salt thereof.

[1429] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease, wherein the compound, or 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.

[1430] In another aspect, the present invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a proliferative disease, wherein the medicament is for simultaneous, separate or sequential administration with a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[1431] In another aspect, the present invention relates to a method for treating a proliferative disease, which method comprises sequentially, separately or simultaneously administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[1432] Any DNA damage response modulator (eg, PARP inhibitor, ATM inhibitor and / or ATR inhibitor) may be used in the combination therapies defined herein.

[1433] Combination therapy with DNA damage response modulators

[1434] The compounds of the present invention are particularly suitable for use in combination with drugs that act as modulators of the DNA damage response, such as PARP inhibitors, ATM inhibitors and ATR inhibitors.

[1435] In one aspect, the invention relates to a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor), or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease.

[1436] In another aspect, the present invention relates to the use of a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof and a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a proliferative disease.

[1437] In another aspect, the present invention relates to a method of treating a proliferative disease in a subject in need thereof, which method comprises administering to the 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) as defined herein, or a pharmaceutically acceptable salt thereof.

[1438] In another aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease, wherein the compound, or 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.

[1439] In another aspect, the present invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a proliferative disease, wherein the medicament is for simultaneous, separate or sequential administration with a DNA damage response modulator (e.g. a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[1440] In another aspect, the present invention relates to a method for treating a proliferative disease, which method comprises sequentially, separately or simultaneously administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof.

[1441] Any DNA damage response modulator (eg, PARP inhibitor, ATM inhibitor and / or ATR inhibitor) may be used in the combination therapies defined herein.

[1442] Probe compounds of the present invention

[1443] In another aspect, the present invention provides a probe compound of formula (I) or subformulas (II) to (I-XLV) as defined herein, or a salt thereof, wherein R 12 or R 13 One of them is a group -LQ or -L as defined herein x -X.

[1444] The probe compound of the present invention is selective for MLH1.

[1445] The linker group L can be any suitable linker moiety that connects the detection moiety Q to the remainder of the probe compound of formula (I) or subformulas (II) to (I-XLV) as defined herein.

[1446] Suitably, the linker group L is 3 to 30 atoms in length, more suitably 4 to 20 atoms in length, even more suitably 5 to 18 atoms in length. In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) defined herein, L is 5 to 12 atoms in length.

[1447] Suitably, L is as defined in any of paragraphs (115) to (146) above. More suitably, L is as defined in any of the numbered paragraphs (139) to (146) above. In a particular group of probe compounds of formula (I) or subformulas (II) to (I-XLV), L is as defined in paragraphs (144), (145) or (146) above.

[1448] The detection moiety Q can be any part of the probe compound of formula (I) that can detect and quantify. As further described below, the probe compound of formula (I) defined herein is designed for displacement assay, whereby the ability of the test compound to displace the probe compound of formula (I) from the ATP binding site of a target protein (e.g., MLH1) can be used to determine the binding affinity of the test compound to the ATP binding site of the target protein. Therefore, the detection moiety Q can be any part that is easy to detect and quantify. In some cases, the detection moiety Q enables any probe compound of formula (I) that is displaced (i.e., "unbound") from the ATP binding site of the target protein to be detected and quantified. In certain embodiments of the invention, this can be achieved by collecting any displaced or "unbound" compound of formula (I) from a test sample and assaying the sample to determine how many unbound probe compounds are present. This in turn will indicate how many probe compounds present in the sample have been replaced by the test compound.

[1449] Therefore, it will be appreciated that the nature of the detection moiety Q is not important, so long as it can be used to determine the amount of the probe compound of Formula (I) present in a sample. Those skilled in the art will be able to select an appropriate detection moiety Q and an appropriate method to detect and quantify the amount of the compound of Formula (I) in a sample, in particular to detect the amount of the probe compound of Formula (I) displaced from the ATP binding site of the target protein by the test compound.

[1450] 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.

[1451] In embodiments where the detection moiety Q is an oligonucleotide, biomolecule, molecular sensor, protein, or peptide, the amount of the oligonucleotide, biomolecule, molecular sensor, protein, or peptide present can be detected and quantified using any suitable technique known in the art. For example, a fluorescently labeled second probe can be used that is capable of specifically binding to the detection moiety Q of the probe compound of Formula (I), and once any excess second probe is removed, the amount of the second probe bound to the detection moiety Q of the compound of Formula (I) can be detected and quantified, thereby enabling the amount of the probe compound of Formula (I) to be determined.

[1452] For example, if Q is an oligonucleotide, a second probe having a suitable detectable label (e.g., a fluorophore or a radioactive label) 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 the sample (and the amount of the probe compound displaced from the ATP binding site of the target protein by the test compound). Similarly, if Q is a protein or peptide, the second probe can be an antibody capable of selectively binding to the protein or peptide and a suitable detectable label, such as a fluorophore or a radioactive label.

[1453] More preferably, the detection moiety Q is a fluorophore. In this case, the compound of formula (I) can be used for fluorescence polarization determination. In one specific 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 dye, FITC, Ru (bpy) 3, rhodamine dyes, acridine orange, and Texas Red. In another group of probe compounds of formula I, the detection moiety Q is a fluorophore selected from the group consisting of AlexaFluor-647, AlexaFluor-633, AlexaFluor-594, AlexaFluor-488, 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.

[1454] Suitably, Q is as defined in any of the above numbered paragraphs (147) to (150). More suitably, Q is as defined in any of the above numbered paragraphs (148) to (150). Most suitably, Q is as defined in the above numbered paragraphs (149) or (150).

[1455] It will be understood that X may be any suitable functional group that is capable of reacting with a functional group present on the detection moiety Q or a compound of formula Q-L2-Y as defined herein to covalently bind the detection moiety to the compound of formula (I), thereby forming a compound of formula (I) as defined herein.

[1456] Those skilled in the art will be familiar with suitable functional groups that can be used to form a covalent bond with a suitable detection moiety. For example, X can be selected from halogen, N3 or ethynyl.

[1457] In a particular embodiment, X is N3 or ethynyl.

[1458] Suitably, X is a functional group capable of reacting with a functional group present on the detection moiety to form a bond or triazole bond between the detection moiety and the compound of formula (I). In a particular embodiment, the bond formed is a triazole bond (which may be formed by click chemistry).

[1459] Suitably, X is as defined in any of the above numbered paragraphs (151) to (156). More suitably, X is as defined in any of the above numbered paragraphs (153) to (156). Most suitably, X is as defined in the above numbered paragraph (156).

[1460] In certain embodiments of the present invention, wherein R 12 or R 13 A compound of formula (I) or a compound of sub-formula (II) to (I-XLV) wherein R 12 or R 13 One of them is the group -L x -X is reacted with a compound of formula (I) or sub-formula (II) to (I-XLV) to form:

[1461] QL y -Y

[1462] in:

[1463] Q is the detection part defined above:

[1464] L y is absent or is a linker group, when group L of the compound of formula I x When covalently bound, the linker group forms the linker L of the compound of formula (I) or the compound of sub-formulae (II) to (I-XLV);

[1465] Y is L capable of reacting with the functional group X present on the compound of formula (I) or sub-formula (II) to (I-XLV) to covalently link Q-L2 to the compound of formula (I) or sub-formula (II) to (I-XLV) x and forming a functional group of -LQ group.

[1466] In one embodiment, L y is a (1-8C)alkylene linker, wherein the alkylene chain optionally further comprises one or more -O-, -C(O)NR located within the alkylene chain and / or at one of its termini q1 -、-NR q1 C(O)-, -C(O)O-, -OC(O-) or triazole ring bond, wherein R q1 is hydrogen or (1-2C)alkyl.

[1467] In another embodiment, L yis a (1-8C)alkylene linker, wherein the alkylene chain optionally further comprises an -O-, -C(O)NR located within the alkylene chain and / or at one of its termini q1 -、-NR q1 C(O)-, -C(O)O-, -OC(O-) or triazole ring bond, wherein R q1 is hydrogen or (1-2C)alkyl.

[1468] In a further embodiment, L y is a (1-5C)alkylene linker.

[1469] In another embodiment, L y is a (1-3C)alkylene linker.

[1470] It should be understood that Y can be a functional group that reacts with the functional group X present on the probe compound of Formula I to convert the group QL y Any suitable functional group which is covalently bonded to a compound of formula I thereby forming a compound of formula I as defined herein.

[1471] Those skilled in the art will be familiar with suitable functional groups that can be used to form a covalent bond with the functional group X on the compound of formula (I) or sub-formula (II) to (I-XLV). For example, Y can be selected from halogen, N3 or ethynyl.

[1472] In a specific embodiment, when X is ethynyl, Y is N3, or when X is N3, Y is ethynyl.

[1473] Suitably, Y is a functional group capable of reacting with a functional group X present on a probe compound of formula (I) or sub-formulas (II) to (I-XLV) to form a bond or a triazole bond. In a specific embodiment, the bond formed is a triazole bond (which can be formed by click chemistry).

[1474] Linker group L x may be any suitable linker moiety that connects the functional group X to the remainder of the probe compound of formula (I) or subformulas (II) to (I-XLV) as defined herein. Suitably, L x As defined in any of the above numbered paragraphs (157) to (161). More suitably, L x As defined in any of the above numbered paragraphs (159) to (161). Most suitably, L x As defined in the above numbered paragraph (161).

[1475] In a specific group of probe compounds of the present invention, the probe compound is a compound of formula (I) or sub-formula (II) to (I-XLV), wherein R 2 、R 3、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,R 11 、R 12 、R 13 and R 14 Each has any of the definitions provided above, provided that R 12 or R 13 One of the groups is:

[1476] -LQ

[1477] wherein L is a linker; and Q is a detection moiety.

[1478] Suitably, in the probe compound of formula (I) or subformulas (II) to (I-XLV), L is a linker as defined in any of the above numbered paragraphs (139) to (146); and Q is a detection moiety as defined in any of the above numbered paragraphs (148) to (150). More suitably, L is a linker as defined in any of the above numbered paragraphs (144), (145) or (146); and Q is a detection moiety as defined in any of the above numbered paragraphs (149) or (150).

[1479] In another group of probe compounds of the present invention, the compound is a compound of formula (I) or sub-formula (II) to (I-XLV) shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 2 、R 3 、R 4 、R 5 ,Y1,Y2,A1,A2,A3,A4,R 11 、R 12 、R 13 and R 14 Each has any of the definitions provided above, provided that R 12 or R 13 One of the groups is:

[1480] -LQ

[1481] Wherein L is a linker and Q is a detection moiety.

[1482] Suitably, in the probe compound of formula (I) or subformulas (II) to (I-XLV), L is a linker as defined in any of the above numbered paragraphs (139) to (146); and Q is a detection moiety as defined in any of the above numbered paragraphs (148) to (150). More suitably, L is a linker as defined in any of the above numbered paragraphs (144), (145) or (146); and Q is a detection moiety as defined in any of the above numbered paragraphs (149) or (150).

[1483] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 2 As defined in paragraph (1) above.

[1484] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 4 As defined in numbered paragraph (5) above.

[1485] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 4 As defined in numbered paragraph (6) above.

[1486] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 4 As defined in numbered paragraph (7) above.

[1487] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 As defined in numbered paragraph (12) above.

[1488] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 As defined in numbered paragraph (13) above.

[1489] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 As defined in numbered paragraph (14) above.

[1490] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (18) above.

[1491] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (19) above.

[1492] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (20) above.

[1493] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 3 and R 4 As defined in numbered paragraph (21) above.

[1494] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 5 As defined in numbered paragraph (23) above.

[1495] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 5 As defined in numbered paragraph (24) above.

[1496] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 6 As defined in numbered paragraph (34) above.

[1497] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 6 As defined in numbered paragraph (35) above.

[1498] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 6 As defined in numbered paragraph (36) above.

[1499] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) defined herein, A1, A2, A3 and A4 are as defined in numbered paragraph (64) above.

[1500] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 11 As defined in numbered paragraph (84) above.

[1501] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 11 As defined in numbered paragraph (85) above.

[1502] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 11 As defined in numbered paragraph (86) above.

[1503] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 12 As defined in numbered paragraph (94) above.

[1504] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 12 As defined in numbered paragraph (95) above.

[1505] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 12 As defined in numbered paragraph (96) above.

[1506] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 13 As defined in numbered paragraph (99) above.

[1507] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 13 As defined in numbered paragraph (100) above.

[1508] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 13 As defined in numbered paragraph (101) above.

[1509] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 14 As defined in numbered paragraph (103) above.

[1510] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R 14 As defined in numbered paragraph (104) above.

[1511] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R14 As defined in numbered paragraph (105) above.

[1512] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R a As defined in numbered paragraph (112) above.

[1513] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R a As defined in numbered paragraph (113) above.

[1514] In a specific group of probe compounds of formula (I) or subformulas (II) to (I-XLV) as defined herein, R a As defined in numbered paragraph (114) above.

[1515] Suitable salts of the probe compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleic acid. In addition, suitable salts of sufficiently acidic compounds of the present invention are alkali metal salts, such as sodium salts or potassium salts, alkaline earth metal salts, such as calcium salts or magnesium salts, ammonium salts or salts with organic bases.

[1516] The present invention also includes probe compounds of the present invention as defined herein, which contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; and O may be in any isotopic form, including 16 O and 18 O and so on.

[1517] It will also be appreciated that certain probe compounds of Formula (I) may exist in solvated as well as unsolvated forms, for example hydrated forms.

[1518] It will also be understood that certain probe compounds of Formula (I) may exhibit polymorphism and that the present invention encompasses all such polymorphic forms.

[1519] Certain 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.

[1520] Synthesis of probe compounds

[1521] In another aspect, the present invention provides a method for synthesizing a probe compound of formula (I) or subformulae (II) to (I-XLV) as defined herein, or a salt thereof.

[1522] The probe compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[1523] In the descriptions of synthetic methods described herein, and in any referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, duration of experiments, and work-up procedures, can be selected by one skilled in the art.

[1524] Those skilled in the art of organic synthesis will appreciate that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[1525] It will be appreciated that during the synthesis of the compounds of the invention in the methods defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undesirable reactions. A skilled chemist will understand when such protection is necessary and how to place such protecting groups in place and then remove them.

[1526] For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green, Protective Groups in Organic Synthesis; Fourth Edition; 2006 (Publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist to be suitable for removing the protecting group in question, the method being selected so as to achieve removal of the protecting group with minimal interference with other groups in the molecule.

[1527] In one aspect, the present invention provides a method for synthesizing a compound of formula I as defined herein, the method comprising: 12 or R 13 One of them is a group -L as defined herein x -X, reacting a compound of formula (I) or sub-formula (II) to (I-XLV) with a compound of formula Q-L2-Y as defined herein to form a compound of formula (I) or sub-formula (II) to (I-XLV); and optionally thereafter:

[1528] (i) removing any protecting groups present;

[1529] (ii) forming a salt of a compound of formula (I) or sub-formulae (II) to (I-XLV); and / or

[1530] (iii) isolating and purifying the compound of formula (I) or sub-formulae (II) to (I-XLV).

[1531] Application of probe compounds

[1532] In one aspect, the present invention provides the use of a probe compound of formula (I) or sub-formulas (II) to (I-XLV) or a salt thereof as defined herein in a displacement assay to determine the binding affinity of a test molecule to the ATP binding site of a target protein.

[1533] In another aspect, the present invention provides a probe compound of formula (I) or subformulas (II) to (I-XLV) 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.

[1534] In one embodiment, the target protein is MLH1.

[1535] Displacement assays are well known in the art. In embodiments of the invention where Q is a fluorophore, the displacement assay is a fluorescence polarization assay. Fluorescence polarization assays are well known in the art.

[1536] The test compound can be any biological or small molecule compound that is to be screened for binding to the ATP binding site of the target protein (eg, MLH1).

[1537] 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:

[1538] (i) incubating the test molecule with the target protein in the presence of a probe compound of formula (I) or subformulas (II) to (I-XLV) or a salt thereof as defined herein; and

[1539] (ii) Determining whether any probe compound is displaced from the ATP binding site of the target protein.

[1540] In one embodiment, the target protein is MLH1.

[1541] Suitably, the assay is a displacement assay. Displacement assays are well known in the art. In embodiments of the invention where Q is a fluorophore, the displacement assay is a fluorescence polarization assay. Fluorescence polarization assays are well known in the art.

[1542] The step of determining whether any probe compound is displaced from the ATP binding site of the target protein suitably comprises detecting whether the test compound results in an increase in the proportion of the probe compound of formula (I) or sub-formulas (II) to (I-XLV) that is not bound to the ATP binding site. This can be achieved by detecting whether the amount of unbound probe compound increases (relative to the control), or if the amount of bound probe compound can be readily detected (e.g. by fluorescence polarization), detecting whether the amount of bound probe compound decreases (again relative to the control).

[1543] The ratio of the probe compound bound to the ATP binding site of the target protein relative to the unbound amount can be determined by techniques known in the art. The specific technique used will depend on the properties of the detection moiety Q in the compound of formula (I) or sub-formula (II) to (I-XLV). Suitably, Q is a fluorophore, and the assay is a fluorescence polarization assay. In this assay, the fluorescence difference caused by the displacement of the probe compound from the ATP binding site of the target protein can be detected, and used to quantify the amount of any displaced probe compound, thereby determining the binding affinity of the test compound to the ATP binding site of the target protein.

[1544] 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:

[1545] (i) incubating the test molecule with the target protein in the presence of a probe compound of formula (I) or subformulas (II) to (I-XLV) or a salt thereof as defined herein; and

[1546] (ii) Determining whether any probe compound is displaced from the ATP binding site of the target protein.

[1547] In one embodiment, the target protein is MLH1.

[1548] Suitably, the method is a displacement assay. Displacement assays are well known in the art. In embodiments of the invention where Q is a fluorophore, the displacement assay is a fluorescence polarization assay. Fluorescence polarization assays are well known in the art.

[1549] The step of determining whether any probe compound is displaced from the ATP binding site of the target protein can be performed in the manner described above.

[1550] In another aspect, the present invention provides an assay for determining the location and / or amount of a target protein present in a biological sample, the assay comprising:

[1551] (i) contacting the biological sample with a probe compound of formula (I) or subformulas (II) to (I-XLV) as defined herein, or a salt thereof; and

[1552] (ii) determining the location and / or amount of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the sample by detecting the location and / or intensity of the detection portion of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the biological sample.

[1553] In another aspect, the present invention provides an assay for determining the location and / or amount of a target protein present in a biological sample, the assay comprising:

[1554] (i) contacting the biological sample with a probe compound of formula (I) or subformulas (II) to (I-XLV) as defined herein, or a salt thereof, wherein R 12 or R 13 One of them is a group -L as defined herein x -X; and

[1555] (ii) contacting the biological sample with a detection moiety Q or a compound of formula Q-L2-Y as defined herein, which is capable of reacting with a functional group X present on a compound of formula (I) or subformulas (II) to (I-XLV) to form a compound of formula (I) or subformulas (II) to (I-XLV) in situ in the biological sample, wherein R 12 or R 13 One is a group -LQ as defined herein;

[1556] (iii) determining the location and / or amount of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the sample by detecting the location and / or intensity of the detection portion of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the biological sample.

[1557] In another aspect, the present invention provides a method for determining the location and / or amount of a target protein present in a biological sample, the method comprising:

[1558] (i) contacting the biological sample with a probe compound of formula (I) or subformulas (II) to (I-XLV) as defined herein, or a salt thereof; and

[1559] (ii) determining the location and / or amount of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the sample by detecting the location and / or intensity of the detection portion of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the biological sample.

[1560] In another aspect, the present invention provides a method for determining the location and / or amount of a target protein present in a biological sample, the method comprising:

[1561] (i) contacting the biological sample with a detection moiety Q or a compound of formula Q-L2-Y as defined herein, which is capable of reacting with a functional group X present on a compound of formula (I) or subformulas (II) to (I-XLV), wherein R 12 or R 13 One of them is a group -L as defined herein x -X, to form in situ in a biological sample a compound of formula (I) or sub-formulae (II) to (I-XLV), wherein R 12 or R 13 One is a group -LQ as defined herein;

[1562] (ii) determining the location and / or amount of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the sample by detecting the location and / or intensity of the detection portion of the compound of formula (I) or sub-formulas (II) to (I-XLV) present in the biological sample.

[1563] In one embodiment, the target protein is MLH1.

[1564] Suitably, the step of contacting the biological sample with a probe compound of formula (I) or sub-formulas (II) to (I-XLV) (step (i) in the above assays and methods) comprises incubating the biological sample with the probe compound under conditions such that the probe compound is able to bind to the ATP binding site of the target protein (e.g. MLH1).

[1565] The distribution of the compound of formula (I) in the biological sample and the mensuration of quantity can be realized by technology known in the art.The specific technique used will depend on the property of detection part Q in the compound of formula (I).Suitably, Q is a fluorophore, and the position of the compound of formula (I) in the sample and the mensuration of quantity can be realized by fluorescence microscope / imaging.The suitable calibration of fluorescence intensity can be used for measuring the amount of the compound of formula (I) in different positions in the sample.

[1566] The assays and methods of the invention defined herein may optionally further comprise one or more washing steps performed after step (i) to remove excess probe compounds of formula (I) or subformulas (II) to (I-XLV) from the biological sample.

[1567] Example

[1568] abbreviation

[1569] ACN stands for acetonitrile

[1570] Boc represents tert-butoxycarbonyl

[1571] CPME stands for cyclopentyl methyl ether

[1572] DAST stands for diethylaminosulfur trifluoride

[1573] DCM stands for dichloromethane

[1574] DIPEA stands for N,N-diisopropylethylamine, Hünig's base

[1575] DMAP stands for 4-(dimethylamino)pyridine

[1576] DME stands for dimethyl ether

[1577] DMF stands for dimethylformamide

[1578] DMSO stands for dimethyl sulfoxide

[1579] DPPF stands for 1,1'-bis(diphenylphosphino)ferrocene

[1580] EDC stands for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1581] EtOAc means ethyl acetate

[1582] FA stands for formic acid

[1583] h represents hours

[1584] HATU stands for (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[1585] HOBT stands for N-hydroxybenzotriazole

[1586] HPLC stands for high pressure liquid chromatography

[1587] IPA stands for isopropyl alcohol

[1588] LAH stands for lithium aluminum hydride

[1589] LCMS stands for liquid chromatography-mass spectrometry

[1590] MI stands for molecular ion

[1591] min means minutes

[1592] MW stands for microwave

[1593] NMM stands for N-methylmorpholine

[1594] NMR stands for Nuclear Magnetic Resonance

[1595] PdCl2(PPh3)2 represents bis(triphenylphosphine)palladium chloride

[1596] Pd(dppf)2Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[1597] (Pd(dba)2) represents bis(dibenzylideneacetone)palladium

[1598] RT stands for room temperature

[1599] SFC stands for supercritical fluid chromatography

[1600] TFAA stands for trifluoroacetic anhydride

[1601] TFA stands for trifluoroacetic acid

[1602] THF stands for tetrahydrofuran

[1603] Dioxane means dioxane 4M HCl in Dioxane means 4M HCl in dioxane solution

[1604] Toluene means toluene

[1605] Acetic anhydride means acetic anhydride

[1606] Acetone means acetone

[1607] Anisole means anisole

[1608] Glycerol means glycerol

[1609] Bispinacoleto diborane means bispinacole diborane

[1610] Boc anhydride means Boc anhydride

[1611] microwave means microwave

[1612] Analytical methods

[1613] Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash chromatography or glass column chromatography was performed using Merck silica gel 230-400 mesh or Interchim PuriFlash HC silica gel columns. Flash chromatography was also performed on combi-flash RF Teledyne Isco or Biotage Isolera machines. Preparative TLC was performed on Merck plates.

[1614] Unless otherwise stated, the solvents were used at around room temperature and the measurements were performed using a Bruker instrument operating at 400 MHz. 1H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million, and conventional abbreviations are used to designate major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

[1615] Liquid chromatography-mass spectrometry method

[1616] Method-A

[1617] Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA high-performance mass spectrometer detector, chromatographic column: Xbridge BEH C18, 50x2.1 mm, 2.5 μm, 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: acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) Flow rate: 1 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; run terminated at t = 4 min (97% A, 3% B) flow rate: 0.8 mL / min, analysis time: 4 min. Mass detector parameters: ionization mode cycled through positive and negative modes, cone voltages of 10 V and 30 V, capillary voltage of 0.8 kV, source and probe temperatures of 120°C and 600°C, respectively.

[1618] Method-B

[1619] Waters Acquity with PDA detector and SQ detector, chromatographic column: X-Bridge BEH C18, 50x2.1mm, 2.5 micron, column temperature: 5°C, mobile phase A: 5mM ammonium bicarbonate in water (pH=7.35), mobile phase B:

[1620] 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 minutes (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 min. Mass detector parameters: ionization mode was cycled through positive and negative modes, cone voltage was 10 V and 30 V, capillary voltage was 3.25 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[1621] Method-C

[1622] Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA high-performance mass spectrometer, chromatographic column: Ymc Tri-art C18, 50 x 2 mm, 1.9 μm, 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: acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) Flow rate: 1 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; run terminated at t = 4 min (97% A, 3% B) flow rate: 0.8 mL / min, analysis time: 4 min. Mass detector parameters: ionization mode cycled through positive and negative modes, cone voltages of 10 V and 30 V, capillary voltage of 0.8 kV, source and probe temperatures of 120°C and 600°C, respectively.

[1623] Method-CA

[1624] Waters Acquity UPLC-MS equipped with Waters DAD and Waters SQD2, chromatographic column: AcquityUPLC HSS C18 1.8um 100x 2.1mm (with guard column), mobile phase A: water containing 0.1% formic acid (high purity, through PureLab Option unit), mobile phase B: acetonitrile containing 0.1% (v / v) formic acid (far UV grade), flow rate: 0.4ml / min, mobile phase gradient details: t=0min (95% A, 5% B); t=0.4min (95% A, 5% B); gradient to t=6.0min (5% A, 95% B); t=6.8min (5% A, 95% B); gradient to t=7min (95% A, 5% B); end of run at t=8min (95% A, 5% B), sample: 0.5-2ul (concentration approximately 0.2-1mg / ml), DAD detector parameters: UV, diode array 210nm-400nm, resolution 1.2nm, mass detector parameters: MS, mass 100-700 in ES+&ES- (300μl / min split to MS).

[1625] Method-D

[1626] Waters Acquity UPLC equipped with a quaternary solvent manager, PDA detector, and SQ detector, chromatographic column: X-Bridge BEH C18, 50*2.1 mm, 2.5 μm, 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: acetonitrile (10:90), mobile phase gradient details: t=0 min (97% A, 3% B) flow rate: 0.8 mL / min; t=0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; gradient to t=2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; gradient to t=3 min (0% A, 100% B) flow rate: 1 mL / min; t=3.5 min (0% A, 100% B) Flow rate: 1 mL / min; gradient to t = 3.51 min (97% A, 3% B), flow rate: 0.8 mL / min; run terminated 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 through positive and negative modes, cone voltages of 10 V and 30 V, capillary voltage of 0.8 kV, source and probe temperatures of 120°C and 400°C, respectively.

[1627] Method-E

[1628] Waters Acquity UPLC with binary solvent manager, PDA detector, and Acquity QDA high-performance mass spectrometer, chromatographic column: Welch Xtimate C18, 50 x 2.1 mm, 1.8 μm, 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: acetonitrile (10:90), mobile phase gradient details: t = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; t = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; gradient to t = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min; gradient to t = 3 min (0% A, 100% B) flow rate: 1 mL / min; t = 3.5 min (0% A, 100% B) Flow rate: 1 mL / min; gradient to t = 3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; run terminated at t = 4 min (97% A, 3% B) flow rate: 0.8 mL / min, analysis time: 4 min. Mass detector parameters: ionization mode cycled through positive and negative modes, cone voltages of 10 V and 30 V, capillary voltage of 0.8 kV, source and probe temperatures of 120°C and 600°C, respectively.

[1629] Method-F

[1630] Waters Acquity UPLC with PDA detector and SQ detector, column: Welch-Xtimate, C18 4.6*50 mm, 5 μm, column 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 minutes (97% A, 3% B), flow rate: 0.5 mL / min, analysis time: 4 minutes. Mass detector parameters: ionization mode cycled through positive and negative modes, cone voltages of 10 V and 30 V, capillary voltage of 3.25 kV, source and probe temperatures of 120°C and 400°C, respectively.

[1631] Method-G

[1632] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: X-Bridge C18 2.1*50mm 3.5μm, column temperature: 5°C, mobile phase A: 5mM 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 minutes (97% A, 3% B), flow rate: 0.5 mL / min, analysis time: 4 minutes. Mass detector parameters: ionization mode cycled through positive and negative modes, cone voltages of 10 V and 30 V, capillary voltage of 0.8 kV, source and probe temperatures of 120°C and 600°C, respectively.

[1633] Method-H

[1634] A Waters 996 photodiode array detector equipped with a Waters Micromass ZQ detector, chromatographic column: XTIMATE C18 5μm 4.6*150mm, column temperature: 35°C, autosampler temperature: 15°C, mobile phase A: Milli Q aqueous solution of 5mM ammonium acetate and 0.1% formic acid (pH=3.50), mobile phase B: methanol. Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), flow rate: -1.0 mL / min, run time: -17 min, UV detection method:...

Claims

1. A compound or a pharmaceutically acceptable salt thereof having structural formula (I) as shown below: in R 2 is hydrogen or fluorine; R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy; R 4 is selected from hydrogen, halogen or cyano; or R 3 and R 4 Connection formation: a fused 5- or 6-membered carbocyclic or heterocyclic ring; fused benzene rings; or a 5-membered or 6-membered heteroaryl ring; each of which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; R 5 It is R 6 OR 6 ; where R 6 is (1-6C)alkyl, (3-8C)cycloalkyl, a 4-7 membered heterocyclyl ring containing one heteroatom selected from N, O or S, phenyl or a 5- or 6-membered heteroaryl; each of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy; or a group having a structure according to formula (A) shown below: in R 7 is hydrogen or (1-3C)alkyl; n is 1 or 2; R 8 is (3-8C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy; Y1 is a bond, -CH2-, -CH2-CH2- or -C(=O)-; Y2 is -CH2-, -C(=O)-, or -CHR y2a -、-CH2-CH2-、-CH2-CHR y2b -or-CHR y2a -CH2-; where R y2a is selected from halogen, cyano, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, and R y2b is selected from halogen, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, provided that when Y1 is a bond, Y2 is -CH2-CH2-, -CH2-CHR y2b -or-CHR y2a -CH2-; A1 is selected from N, CH or CR 11 ; A2 is selected from N, CH or CR 12 ; A3 is selected from N, CH or CR 13 ; A4 is selected from N, CH or CR 14 ; The condition is that only one or two of A1, A2, A3 or A4 can be N; R 11 is cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy group is optionally substituted by one or more halogen or (1-2C)alkoxy groups; or R 11 Yes-(CHR z ) a -Z 11 , in: R z is hydrogen or methyl; a is 0 or 1; and Z 11 is - OR 15 、R 15a 、 - NR 16 R 17 、 - C(O)NR 16 R 17 or - NR 18 C(O)R 19 ; in R 15 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-7C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-8 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 2; R 15a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-7C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-8 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 2; R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-7C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 8-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0, 1 or 2; or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 18 is hydrogen or (1-2C)alkyl; R 19 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR x ) d -(3-7C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4-8 membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl]; where R x is hydrogen or methyl; and d is 0 or 1; where R 11 、R 15 、R 15a 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace; R 12 Select one of the following options: (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or R 12 Yes-(CHR v ) d -Z 12 , in: R v is hydrogen or methyl; d is 0 or 1; and Z 12 is - OR 20 , R 20a , -NR 21 R 22 , -C(O)NR 21 R 22 or -NR 23 C(O)R 24 ; where R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen or methyl, and e is 0, 1, 2 or 3; R 20a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen or methyl, and e is 0, 1, 2 or 3; R 21 and R 22 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl], wherein R q is hydrogen or methyl, and f is 0 or 1; or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 23 is hydrogen or (1-2C)alkyl; R 24 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4-8 membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], wherein R p is hydrogen or methyl, and g is 0 or 1; where R 12 、R 20 、R 20a 、R 21 、R 22 、R 23 or R 24 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace; R 13 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or R 13 Yes-(CHR o ) h -Z 13 , in: R o is hydrogen or methyl; h is 0 or 1; and Z 13 is - OR 25 , R 25a , -NR 26 R 27 , -C(O)NR 26 R 27 or -NR 28 C(O)R 29 ; where R 25 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n is hydrogen or methyl, and i is 0, 1 or 2; R 25a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above; R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4- to 8-membered heterocyclyl] or -(CHR m ) j -[5- or 6-membered heteroaryl], wherein R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 28 is hydrogen or (1-2C)alkyl; R 29 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-8 membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], wherein R l is hydrogen or methyl, and k is 0 or 1; where R 13 、R 25 、R 25a 、R 26 、R 27 、R 28 or R 29 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace; R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or R 14 Yes-(CHR k ) m -Z 14 , where R k is hydrogen or methyl; wherein m is 0 or 1; and Z 14 is - OR 30 、R 30a 、 - NR 31 R 32 、 - C(O)NR 31 R 32 or - NR 33 C(O)R 34 ; where R 30 is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4-8 membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], wherein R j is hydrogen or methyl, and o is 0 or 1; R 30a is (1-4C)alkyl, (3-7C)cycloalkyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3-7C)cycloalkyl, -(CHR j ) o -[4-8 membered heterocyclyl] or -(CHR j ) o -[5- or 6-membered heteroaryl], wherein R j is hydrogen or methyl, and o is 0 or 1; R 31 and R 32 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 8 membered heteroaryl, -(CHR i ) p -(3-7C)cycloalkyl, -(CHR i ) p -[4- to 6-membered heterocyclyl] or -(CHR i ) p -[5- or 8-membered heteroaryl], wherein R i is hydrogen or methyl, and p is 0 or 1; or R 31 and R 32 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 33 is hydrogen or (1-2C)alkyl; R 34 is (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR h ) q -(3-7C)cycloalkyl, -(CHR h ) q -[4-8 membered heterocyclyl] or -(CHR h ) q -[5- or 6-membered heteroaryl], wherein R h is hydrogen or methyl, and q is 0 or 1; where R 14 、R 30 、R 30a 、R 31 、R 32 、R 33 or R 34 , or when R 31 and R 32 Any ring formed when connected, optionally with one or more R a replace; And each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-4C)alkyl or a group -L 1 -X 1 -Q 1 in: L 1 Absent or (1-2C)alkylene; X 1 Not present or selected from -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-, where R 14 is hydrogen or (1-2C)alkyl; Q 1 selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl or (3-6C)cycloalkyl; When Q 1 When Q is (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl or (3-6C)cycloalkyl, 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy; And where R 12 or R 13 One of the groups is optionally: -LQ or -L x -X Where L is the linker; L x It is a joint; X is a functional group; and Q is the detection part.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 2 It's hydrogen.

3. The compound according to claim 1 or claim 2, wherein the compound is a compound having one of the following formulae (II) to (I-XLV) or a pharmaceutically acceptable salt thereof: where R 3 、R 4 、R 5 , Y1, Y2, A1, A2, A3 and A4 are each as defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy; or R 3 and R 4 The rings are joined to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 3 is selected from halogen, cyano, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy; or R 3 and R 4 The rings are linked to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, hydroxy, cyano, (1-2C)alkyl, (1-2C)fluoroalkyl, (1-2C)alkoxy or (1-2C)fluoroalkoxy.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 3 is selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; or R 3 and R 4 The rings are joined to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 The groups are joined to form a fused 5- or 6-membered carbocyclic or heterocyclic ring, which is optionally further substituted with halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 The rings are connected to form a fused 5- or 6-membered carbocyclic or heterocyclic ring.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 3 is selected from halogen, cyano, methyl, difluoromethyl, trifluoromethyl or methoxy; or R 3 and R 4 The groups are linked to form a fused 5- or 6-membered cycloalkyl ring.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 5 Yes-OR 6 .

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 5 Yes-OR 6 ,in: (i)R 6 is (1-6C)alkyl, (3-6C)cycloalkyl or a 4-6 membered heterocyclyl ring containing one heteroatom selected from N, O or S, or a group having a structure according to formula (A) as shown below: in R 7 is hydrogen or (1-3C)alkyl; n is 1 or 2; R 8 is (3-8C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or 9- or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy, and wherein any 4- to 6-membered heterocyclyl optionally contains 1 or 2 additional bridge atoms; (ii)R 6 is a (1-4C)alkyl group or a group having a structure according to formula (A) shown below: in R 7 is hydrogen or (1-2C)alkyl; n is 1 or 2; R 8 is (3-6C)cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or 9- or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of hydroxy, cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein any 4- to 6-membered heterocyclyl optionally contains 1 additional bridge atom; (iii)R 6 is a (1-3C)alkyl group or a group having a structure according to formula (A) shown below: in R 7 is hydrogen or methyl; n is 1; R 8 is (3-6C)cycloalkyl, phenyl, 6-membered heterocyclyl, 6-membered heteroaryl, or 9-membered or 10-membered fused bicyclic heteroaryl, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy; (iv)R 6 is methyl, ethyl or a group having a structure according to formula (A) shown below: in R 7 is hydrogen or methyl; n is 1; R 8 is cyclopropyl, cyclohexyl, phenyl, 6-membered heterocyclic group, pyridyl, benzimidazole or quinoline, each of which is optionally substituted by one or more R 9 Replace; wherein each R 9 independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy; or (v)R 6 is methyl or a group having a structure according to formula (A) shown below: in R 7 It is hydrogen; n is 1; R 8 is cyclopropyl or phenyl. (vi)R 6 is a group having a structure according to formula (A) shown below: in R 7 It is hydrogen; n is 1; R 8 It is phenyl.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: (i) Y1 is a bond, -CH2- or -CH2-CH2-; and / or (ii) Y2 is -CH2-, -CHR y2a -、-CH2-CH2-、-CH2-CHR y2b -or-CHR y2a -CH2-; where R y2a is selected from halogen, methyl or hydroxymethyl, and R y2b is selected from halogen, cyano, hydroxy, methyl, methoxy, CF3, -OCF3 or hydroxymethyl, provided that when Y1 is a bond, Y2 is -CH2-CH2-, -CH2-CHR y2b -or-CHR y2a -CH2-; or (iii) Y2 is -CH2- or -CH2-CH2-, provided that when Y1 is a bond, Y2 is -CH2-CH2-.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A1, A2, A3 or A4 is selected from one of the following options: (i) A1 is selected from N, CH or CR 11 ; A2 is selected from N, CH or CR 12 ; A3 is selected from N, CH or CR 13 ; A4 is selected from N, CH or CR 14 ; The condition is that only one of A1, A2, A3 or A4 can be N. (ii) A1 is selected from CH or CR 11 ; A2 is selected from N, CH or CR 12 ; A3 is selected from N, CH or CR 13 ; A4 is selected from N, CH or CR 14 ; The condition is that only one of A2, A3 or A4 can be N; (iii) A1 is CR 11 ; A2 is selected from N, CH or CR 12 ; A3 is selected from N, CH or CR 13 ; A4 is selected from N, CH or CR 14 ; The condition is that only one of A2, A3 or A4 can be N; (iv) A1 is CR 11 ; A2 is selected from N or CH; A3 is selected from N, CH or CR 13 ; A4 is selected from N or CH; The condition is that only one of A2, A3 or A4 can be N; (V)A1 is CR 11 ; A2 is CH; A3 is CH or CR 13 ; A4 is CH; (vi) A1 is CR 11 ; A2 is CH; A3 is CH; A4 is CH; (vii) A1 is CH; A2 is CR 12 ; A3 is CH; A4 is CH; or (viii) A1 is CH; A2 is CH; A3 is CR 13 ; A4 is CH.

14. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3 or A4 is selected from one of the following options: (i) A1 is CH or CR 11 ; A2 is CH; A3 is CH or CR 13 ; A4 is CH; (ii) A1 is CR 11 ; A2 is CH; A3 is CH; A4 is CH; (iii) A1 is CH; A2 is CR 12 ; A3 is CH; A4 is CH; or (iv) A1 is CH; A2 is CH; A3 is CR 13 ; A4 is CH.

15. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein A1 is CH or CR 11 ; A2 is CH; A3 is CH or CR 13 ;and A4 is CH.

16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: (A)R 11 is cyano, halogen or optionally substituted by one or more R a substituted (1-2C)alkyl; or -(CHR z ) a -Z 11 , where R z is hydrogen or methyl; where a is 0 or 1; and Z 11 is - OR 15 、 - NR 16 R 17 、 - C(O)NR 16 R 17 or - NR 18 C(O)R 19 ; where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1 or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring; R 18 is hydrogen or (1-2C)alkyl; R 19 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclic group, 5 or 6 membered heteroaryl, -(CHR x ) d -(3-6C)cycloalkyl, -(CHR x ) d -phenyl, -(CHR x ) d -[4-6 membered heterocyclyl] or -(CHR x ) d -[5- or 6-membered heteroaryl]; where R x is hydrogen or methyl; and d is 0 or 1; where R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (B)R 11 is cyano or -(CHR z ) a -Z 11 , where R z is hydrogen or methyl; where a is 0 or 1; and Z 11 Yes-OR 15 、-NR 16 R 17 or -NR 18 C(O)R 19 ; where R 15 is (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR y ) b -(3-6C)cycloalkyl, -(CHR y ) b -phenyl, -(CHR y ) b -[4-6 membered heterocyclyl] or -(CHR y ) b -[5- or 6-membered heteroaryl], wherein R y is hydrogen or methyl, and b is 0 or 1; R 16 and R 17 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR w ) c -(3-6C)cycloalkyl, -(CHR w ) c -phenyl, -(CHR w ) c -[4- to 6-membered heterocyclyl] or -(CHR w ) c -[5- or 6-membered heteroaryl], wherein R w is hydrogen or methyl, and c is 0 or 1 or R 16 and R 17 connected so that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring; R 18 is hydrogen or (1-2C)alkyl; R 19 is (1-6C)alkyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5- or 6-membered heteroaryl, or -(CHR x ) d -(3-6C)cycloalkyl; where R x is hydrogen or methyl; and d is 0 or 1; where R 15 、R 16 、R 17 、R 18 or R 19 Each of the, or when R 16 and R 17 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (C)R 11 Yes-(CHR z ) a -Z 11 , where R z is hydrogen; where a is 0 or 1; and Z 11 Yes: -OR 15 , where R 15 is (1-4C)alkyl; or -NHR 17 , where R 17 Selected from: (i) Groups of formula (A), (B), (C) or (D): in W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl; R W1C 、R W1D and R W1E is selected from hydrogen or methyl, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace; W2 is selected from O, NR w2 , S or S(O)2, where R w2 is selected from hydrogen, (1-4C)alkyl or (2-4C)alkanoyl; and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace; where R a As defined in claim 1; (ii) a bridged form of the above general formulae (C) and (D), optionally selected from the following general formulae (E) to (J) wherein Y4 is selected from -CH2-, -CH2CH2-, and each of formulae (E), (F), (G), (H) and (J) is optionally replaced by one or more R a replace; where R a As defined in claim 1; (iii) a group of the following formula (K), (L) or (M): in: R W3 is selected from hydrogen or (1-2C)alkyl; W3, W4 and W5 are selected from N or CR w4 , where R w4 is hydrogen, halogen, (1-2C)alkyl or (1-2C)alkoxy; One of W6 and W7 is N, the other is CR w5 , W8 is N or CR w5 , where R w5 is hydrogen, halogen, (1-2C)alkyl or (1-2C)alkoxy; W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one or two of them are N; (D)R 11 Yes-(CHR z ) a -Z 11 , where R z is hydrogen; where a is 0 or 1; and Z 11 Yes: -OR 15 , where R 15 is (1-3C)alkyl; or -NHR 17 , where R 17 Selected from: (i) Groups of formula (A), (B), (C) or (D): in W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl; R W1C 、R W1D and R W1E Selected from hydrogen, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace; W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace; where R a As defined in claim 1; (ii) a bridged form of the above formulae (C) and (D), optionally selected from one of the following formulae (E) to (J): wherein Y4 is selected from -CH2-, -CH2CH2-, and each of formulae (E), (F), (G), (H) and (J) is optionally replaced by one or more R a replace; where R a As defined in claim 1; (iii) a group of the following formula (K), (L) or (M): in: R W3 is selected from hydrogen or (1-2C)alkyl; W3, W4 and W5 are selected from N or CH; One of W6 and W7 is N, the other is CH, and W8 is N or CH; W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one of them is N. (E)R 11 Yes-(CHR z ) a -Z 11 , where R z is hydrogen; where a is 0 or 1; and Z 11 Yes: -OR 15 , where R 15 is (1-2C)alkyl; or -NHR 17 , where R 17 is a group of formula (A), (B), (C) or (D): in W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl; R W1C 、R W1D and R W1E Selected from hydrogen, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace; W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace; where R a as defined in claim 1; or A group of the following formula (K), (L) or (M): in: R W3 is selected from hydrogen or methyl; W3, W4 and W5 are selected from N or CH; One of W6 and W7 is N, the other is CH, and W8 is N or CH; W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one of them is N; or (F)R 11 It's Z 11 , Z 11 Yes: -OR 15 , where R 15 is (1-2C)alkyl; or -NHR 17 , where R 17 Selected from: Groups of formula (A), (B), (C), (D) or (M): in W1 is selected from OR w1a or NR w1a R w1b , where R w1a and R w1b are each independently selected from hydrogen or (1-2C)alkyl; R W1C 、R W1D and R W1E Selected from hydrogen, or R W1C and R W1D or R W1D and R W1E are linked so that together with the carbon atoms to which they are linked they form a (4-6C)cycloalkyl ring or a 5- or 6-membered heterocyclyl ring, each of which is optionally substituted by one or more R a replace; W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; and each of formulae (B), (C) and (D) is optionally replaced by one or more R a replace; where R a As defined in claim 1; W9, W 10 、W 11 and W 12 Select N or CR w6 , where R w6 is hydrogen, halogen, (1-2C) alkyl or (1-2C) alkoxy; provided that W9, W 10 、W 11 and W 12 Only one of them is N; (G)R 11 It's Z 11 , Z 11 Yes: -OR 15 , where R 15 is methyl; or -NHR 17 , where R 17 Selected from: Groups of formula (B), (C), (D) or (M): in W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; and each of formulae (B), (C) and (D) is optionally substituted with oxo (=O); W9, W 10 、W 11 and W 12 is selected from N or CH; provided that W9, W 10 、W 11 and W 12 Only one of them is N. (H)R 11 It's Z 11 , Z 11 Yes: -OR 15 , where R 15 is methyl; or -NHR 17 , where R 17 Selected from: Groups of formula (B), (C) or (D): in W2 is selected from O, NR w2 or S(O)2, where R w2 is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; And each of formulae (B), (C) and (D) is optionally substituted with oxo (=O). (I)R 11 It's Z 11 , Z 11 Yes-NHR 17 , where R 17 Selected from: Groups of formula (B), (C) or (D): in W2 is O; and each of formulae (B), (C) and (D) is optionally substituted with oxo (=O); (J)R 11 It's Z 11 , Z 11 Yes-NHR 17 , where R 17 Selected from: A group of the following formula (B): in W2 is O.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: (A)R 12 Select one of the following options: (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or R 12 Yes-(CHR v ) d -Z 12 where R v is hydrogen or methyl; where d is 0 or 1; and Z 12 is - OR 20 , - NR 21 R 22 , - C(O)NR 21 R 22 or - NR 23 C(O)R 24 ; where R 20 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR u ) e -(3-7C)cycloalkyl, -(CHR u ) e -phenyl, -(CHR u ) e -[4-8 membered heterocyclyl] or -(CHR u ) e -[5- or 6-membered heteroaryl], wherein R u is hydrogen, and e is 0, 1 or 2; R 21 and R 22 Each is independently selected from hydrogen, (1-6C) alkyl, (3-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR q ) f -(3-7C)cycloalkyl, -(CHR q ) f -phenyl, -(CHR q ) f -[4- to 8-membered heterocyclyl] or -(CHR q ) f -[5- or 6-membered heteroaryl], wherein R q is hydrogen or methyl, and f is 0 or 1; or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 23 is hydrogen or methyl; R 24 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR p ) g -(3-7C)cycloalkyl, -(CHR p ) g -phenyl, -(CHR p ) g -[4-8 membered heterocyclyl] or -(CHR p ) g -[5- or 6-membered heteroaryl], wherein R p is hydrogen or methyl, and g is 0 or 1; where R 20 、R 21 、R 22 、R 23 or R 24 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (B)R 12 Select one of the following options: (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or (ii) When R 11 Not a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or R 12 Yes-(CHR v ) d -Z 12 where R v is hydrogen; where d is 0 or 1; and Z 12 Yes-OR 20 、-NR 21 R 22 or -C(O)NR 21 R 22 ; where R 20 is (1-4C)alkyl; R 21 and R 22 each independently selected from hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, a carbon-linked 4- to 8-membered heterocyclyl, or a 5- or 6-membered heteroaryl; or R 21 and R 22 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; where R 20 、R 21 or R 22 Each of the, or when R 21 and R 22 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (C)R 12 Select one of the following options: (i) When R 11 It is a group -(CHR z ) a -Z 11 When R 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or (ii) When R 11 Not-(CHR z ) a -Z 11 When the group is 12 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups; (D)R 12 is selected from fluorine, chlorine, (1-2C)alkyl or (1-2C)alkoxy; or (E)R 12 is fluorine, chlorine or (1-2C)alkoxy.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: (A)R 13 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or R 13 Yes-(CHR o ) h -Z 13 , where R o is hydrogen or methyl; where h is 0 or 1; and Z 13 is - OR 25 、R 25a 、-NR 26 R 27 、-C(O)NR 26 R 27 or - NR 28 C(O)R 29 ; where R 25 is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n is hydrogen or methyl, and i is 0 or 1; R 25a is (1-4C)alkyl, (3-7C)cycloalkyl, phenyl, 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR n ) i -(3-7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above; R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, 5 or 8 membered heteroaryl, -(CHR m ) j -(3-7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4- to 6-membered heterocyclyl] or -(CHR m ) j -[5- or 8-membered heteroaryl], wherein R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 28 is hydrogen or methyl; R 29 is (1-6C)alkyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-8 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR l ) k -(3-7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-8 membered heterocyclyl] or -(CHR l ) k -[5- or 6-membered heteroaryl], wherein R l is hydrogen or methyl, and k is 0 or 1; where R 25 、R 25a 、R 26 、R 27 or R 29 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace; where R a as defined in claim 1; or (B)R 13 is selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl moiety is optionally substituted by one or more halogen or (1-2C)alkoxy, or R 13 Yes-(CHR o ) h -Z 13 , where R o is hydrogen or methyl; where h is 0 or 1; and Z 13 Yes-OR 25 、R 25a 、-NR 26 R 27 or -C(O)NR 26 R 27 ; where R 25 is (1-4C)alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR n ) i -[4-8 membered heterocyclyl], wherein R n is hydrogen or methyl, i is 0 or 1; R 25a is (1-4C)alkyl, phenyl, 4-8 membered heterocyclic group, 5 or 6 membered heteroaryl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n and i is as defined above; R 26 and R 27 Each is independently selected from hydrogen, (1-6C) alkyl, carbon-linked 4-8 membered heterocyclic group or -(CHR m ) j -[4- to 8-membered heterocyclyl], wherein R m is hydrogen or methyl, and j is 0 or 1; or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; where R 25 、R 25a 、R 26 or R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (C)R 13 Yes-(CHR o ) h -Z 13 , where R o is hydrogen or methyl; where h is 0 or 1; and Z 13 Yes-OR 25 、R 25a or -NR 26 R 27 ; where R 25 is (1-4C)alkyl; R 25a is a 4-8 membered heterocyclic group, a 5 or 6 membered heteroaryl group, -(CHR n ) i -[4-8 membered heterocyclyl] or -(CHR n ) i -[5- or 6-membered heteroaryl], wherein R n is hydrogen, and i is 1 or 2; R 26 and R 27 are each independently selected from hydrogen or (1-6C)alkyl; or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; where R 25 、R 25a 、R 26 or R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (D)R 13 Yes-(CHR o ) h -Z 13 , where R o is hydrogen or methyl; where h is 0 or 1; and Z 13 Yes-OR 25 or -NR 26 R 27 ; where R 25 is (1-4C)alkyl; R 26 and R 27 are each independently selected from hydrogen or (1-6C)alkyl; or R 26 and R 27 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; where R 25 、R 26 、R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1; (E)R 13 Yes-(CHR o ) h -Z 13 , where R o is hydrogen; where h is 0 or 1; and Z 13 Yes-OR 25 or -NR 26 R 27 ; where R 25 is (1-2C)alkyl; R 26 and R 27 are each independently selected from hydrogen or (1-2C)alkyl; where R 25 、R 26 、R 27 Each of the, or when R 26 and R 27 Any ring formed when connected, optionally with one or more R a replace; where R a As defined in claim 1.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: (i)R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups, or R 14 Yes-(CHR k ) m -Z 14 , where R k is hydrogen; wherein m is 0 or 1; and Z 14 is - OR 30 , - NR 31 R 32 , - C(O)NR 31 R 32 or - NR 33 C(O)R 34 ; where R 30 is (1-4C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclic group, -(CHR j ) o -(3-7C)cycloalkyl or -(CHR j ) o -[4-8 membered heterocyclyl], wherein R j is hydrogen or methyl, o is 0 or 1; R 31 and R 32 Each is independently selected from hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-linked 4-8 membered heterocyclic group, (CHR i ) p -(3-7C)cycloalkyl or -(CHR i ) p -[4-8 membered heterocyclyl], wherein R i is hydrogen or methyl, and p is 0 or 1 or R 31 and R 32 connected so that they form, together with the nitrogen atom to which they are attached, a 4-8 membered heterocyclic ring; R 33 is hydrogen or methyl; R 34 is (1-6C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-8 membered heterocyclic group, -(CHR h ) q -(3-7C)cycloalkyl or -(CHR h ) q -[4-8 membered heterocyclyl], wherein R h is hydrogen or methyl, q is 0 or 1; where R 30 、R 31 、R 32 or R 34 , or when R 31 and R 32 Any ring formed when connected, optionally with one or more R a replace; where R a as defined in claim 1; or (ii)R 14 is selected from cyano, halogen, (1-2C)alkyl, (1-2C)alkoxy, wherein any (1-2C)alkyl or (1-2C)alkoxy is optionally substituted by one or more halogen or (1-2C)alkoxy groups.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: (i) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-4C)alkyl or a group -L 1 -X 1 -Q 1 in: L 1 Absent or (1-2C)alkylene; X 1 Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)-、-NR 14 -、-SO2N(R 14 )-or-N(R 14 )SO2-, where R 14 is hydrogen or (1-2C)alkyl; Q 1 selected from the group consisting of hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; When Q 1 When Q is (1-4C)alkyl or (3-6C)cycloalkyl, 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl or (1-3C)haloalkoxy; (ii) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group -L 1 -X 1 -Q 1 in: L 1 Absent or (1-2C)alkylene; X 1 Not present or selected from -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)-、-NR 14 -、-SO2N(R 14 )-or-N(R 14 )SO2-, where R 14 is hydrogen or (1-2C)alkyl; Q 1 selected from the group consisting of hydrogen, (1-2C)alkyl or (3-6C)cycloalkyl; When Q 1 When Q is (1-2C)alkyl or (3-6C)cycloalkyl, 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of hydroxy, halogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; (iii) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group -L 1 -X 1 -Q 1 in: L 1 Absent or (1-2C)alkylene; X 1 Not present or selected from -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 - a group consisting of R 14 is hydrogen or (1-2C)alkyl; Q 1 is selected from the group consisting of hydrogen or (1-2C)alkyl; or When Q 1 When it is (1-2C)alkyl, Q 1 Optionally one or more Q a Substitute, where each Q a independently selected from the group consisting of hydroxy, halogen, or (1-2C)alkoxy; (iv) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group -L 1 -X 1 -Q 1 in: L 1 does not exist; X 1 Not present or selected from -O-, -C(O)-, -S(O) 0-2 -、-C(O)-N(R 14 )-、-N(R 14 )-C(O)- or -NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl; Q 1 selected from the group consisting of hydrogen or (1-2C)alkyl; When Q 1 When it is (1-2C)alkyl, Q 1 Optionally one or more Q a Substitute, where each Q a It is methoxy; (v) Each R a are independently selected from the group consisting of oxo, halogen, cyano, hydroxy, (1-2C)alkyl or a group -L 1 -X 1 -Q 1 in: L 1 does not exist; X 1 Absent or selected from -O-, -C(O)- or -NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl; Q 1 selected from the group consisting of hydrogen or (1-2C)alkyl; When Q 1 When it is (1-2C)alkyl, Q 1 Optionally one or more Q a Substitute, where each Q a is methoxy; or (vi) Each R a Independently selected from the group consisting of: oxo or -L 1 -X 1 -Q 1 in: L 1 does not exist; X 1 Absent or selected from -O-, -C(O)- or -NR 14 - a group consisting of R 14 is hydrogen or (1-2C)alkyl; Q 1 selected from the group consisting of hydrogen or (1-2C)alkyl; When Q 1 When it is (1-2C)alkyl, Q 1 Optionally one or more Q a Substitute, where each Q a It's a methoxy group.

21. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following: (S)-(2-(Benzyloxy)-6-hydroxy-4-methoxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-6-hydroxy-4-methoxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-((3-methoxybenzyl)oxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((dimethylamino)methyl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone 1-(3-((2-(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)azetidin-1-yl)ethan-1-one (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone (4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-((4-methoxybenzyl)oxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-((4-methoxybenzyl)oxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one (S)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one (R)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)-1-methylpyrrolidin-2-one (R)-3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)-1-methylpyrrolidin-2-one 3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)dihydrofuran-2(3H)-one 3-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)amino)dihydrofuran-2(3H)-one (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(6-((1H-imidazol-1-yl)methyl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((dimethylamino)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(6-((1H-imidazol-1-yl)methyl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-methoxy-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-5-yl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-4-yl)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-5-yl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(1-methyl-1H-imidazol-4-yl)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone 2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((2-methoxyethyl)amino)isoindolin-2-yl)methanone 2-((2-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxybenzoyl)isoindolin-4-yl)amino)-N,N-dimethylacetamide (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-(dimethylamino)ethoxy)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone ((2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((1-methylazetidin-3-yl)amino)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((2-methoxyethyl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-s(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpiperidin-4-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((4-methylpiperazin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((4-methylpiperazin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (7-((1H-imidazol-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone (6-((1H-imidazol-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone (5-((1H-imidazol-1-yl)methyl)isoindolin-2-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2-((dimethylamino)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(3-((dimethylamino)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpyrrolidin-3-yl)oxy)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpyrrolidin-3-yl)oxy)isoindolin-2-yl)methanone 2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylazetidin-3-yl)oxy)isoindolin-2-yl)methanone (4-(Difluoromethyl)-2-hydroxy-6-(pyridin-2-ylmethoxy)phenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone (2-(Cyclopropylmethoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(pyridin-4-yloxy)isoindolin-2-yl)methanone (2-(Cyclopropylmethoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpiperidin-4-yl)oxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((1-methylazetidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylazetidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-morpholinoethoxy)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-(4-methylpiperazin-1-yl)ethoxy)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(cyclopentylamino)-6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-(methylamino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-(difluoromethyl)-6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone ((S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(2-methoxyethoxy)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((tetrahydro-2H-pyran-4-yl)oxy)isoindolin-2-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone 2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(4-(pyrimidin-5-ylamino)isoindoline-2-carbonyl)benzonitrile (R)-4-(4-((1-acetylpyrrolidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile (S)-4-(4-((1-acetylpyrrolidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile (R)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile or (S)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(4-((oxazol-4-ylmethyl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(4-(((tetrahydrofuran-3-yl)methyl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(4-methoxyisoindoline-2-carbonyl)benzonitrile (R)-3-(Benzyloxy)-5-hydroxy-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzonitrile (R)-3-(Benzyloxy)-5-hydroxy-4-(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (S)-3-(Benzyloxy)-5-hydroxy-4-(6-methoxy-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-4-(5-((dimethylamino)methyl)isoindoline-2-carbonyl)-5-hydroxybenzonitrile 4-(4-((1-acetylpiperidin-4-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile (R)-4-(4-((1-acetylpiperidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile (S)-4-(4-((1-acetylpiperidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile 3-(Benzyloxy)-5-hydroxy-4-(4-((5-oxotetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(4-((1-methylazetidin-3-yl)amino)isoindolin-2-yl)methanone 2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(2-((dimethylamino)methyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone (2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone 1-(3-((2-(2-(Benzyloxy)-4-fluoro-6-hydroxybenzoyl)isoindolin-4-yl)amino)azetidin-1-yl)ethan-1-one (2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-fluoro-6-hydroxyphenyl)(5-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(4-(oxetan-3-ylamino)isoindoline-2-carbonyl)benzonitrile (S)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-2-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (R)-3-(Benzyloxy)-5-hydroxy-4-(4-((1-methyl-2-oxopyrrolidin-3-yl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxybenzonitrile (R)-3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylpyrrolidin-3-yl)oxy)isoindoline-2-carbonyl)benzonitrile (S)-3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylpyrrolidin-3-yl)oxy)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylazetidin-3-yl)oxy)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-((1-methylpiperidin-4-yl)oxy)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-(2-methoxyethoxy)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-((tetrahydro-2H-pyran-4-yl)oxy)isoindoline-2-carbonyl)benzonitrile 3-Hydroxy-4-(5-((1-methylazetidin-3-yl)oxy)isoindoline-2-carbonyl)-5-(pyridin-2-ylmethoxy)benzonitrile 3-Hydroxy-4-(4-(oxetan-3-ylamino)isoindoline-2-carbonyl)-5-(pyridin-2-ylmethoxy)benzonitrile (S)-3-Hydroxy-5-(pyridin-2-ylmethoxy)-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (S)-3-(Benzyloxy)-5-hydroxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (S)-3-Hydroxy-5-methoxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (S)-3-(Cyclopropylmethoxy)-5-hydroxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile (R)-3-(Benzyloxy)-5-hydroxy-4-(4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(isoindoline-2-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-methoxyisoindoline-2-carbonyl)benzonitrile (R)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxybenzonitrile (S)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxybenzonitrile 4-(4-((1-acetylazetidin-3-yl)amino)isoindoline-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile (S)-3-(Benzyloxy)-5-hydroxy-4-(8-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzonitrile (R)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)-5-hydroxybenzonitrile (S)-3-(Benzyloxy)-4-(6-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)isoindoline-2-carbonyl)-5-hydroxybenzonitrile (R)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-4-chloro-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-(Benzyloxy)-6-hydroxy-4-(trifluoromethyl)phenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone (S)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-(2-(dimethylamino)ethoxy)-8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-(piperidin-4-yloxy)isoindolin-2-yl)methanone 3-(Benzyloxy)-4-(6-((dimethylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)-5-hydroxybenzonitrile 3-(Benzyloxy)-5-hydroxy-4-(6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)benzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone (S or R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(6-((tetrahydrofuran-3-yl)amino)indoline-1-carbonyl)benzonitrile 3-(Benzyloxy)-5-hydroxy-4-(5-((tetrahydrofuran-3-yl)amino)indoline-1-carbonyl)benzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone (S or R)-(2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(5-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(7-((1-methylpiperidin-4-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-3-carbonyl)benzonitrile hydroformate (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(7-((1-methylpiperidin-4-yl)oxy)-1,2,4,5-tetrahydro-3H-benzo[d]azepan-3-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(6-morpholino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)benzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-morpholino-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone 4-(6-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)-3-(benzyloxy)-5-hydroxybenzonitrile hydroformate (6-Amino-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)(2-(benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)methanone hydroformate 3-(Benzyloxy)-4-(4-(2-(dimethylamino)ethoxy)indoline-1-carbonyl)-5-hydroxybenzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-(2-(dimethylamino)ethoxy)indolin-1-yl)methanone 3-(Benzyloxy)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-5-hydroxybenzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methanone 3-(Benzyloxy)-4-(2-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-5-hydroxybenzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2-(2-(dimethylamino)ethoxy)-4-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone 3-(Benzyloxy)-5-hydroxy-4-(6-((tetrahydrofuran-3-yl)amino)-1,2,3,4-tetrahydroquinoline-1-carbonyl)benzonitrile (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(6-((tetrahydrofuran-3-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)-4-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methanone (2-(Benzyloxy)-4-(difluoromethyl)-6-hydroxyphenyl)(4-((tetrahydrofuran-3-yl)amino)indolin-1-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-(isoquinolin-6-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(4-(Difluoromethyl)-2-hydroxy-6-(isoquinolin-7-ylmethoxy)phenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (S)-(2-((1H-benzo[d]imidazol-2-yl)methoxy)-4-(difluoromethyl)-6-hydroxyphenyl)(8-((tetrahydrofuran-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

22. A pharmaceutical composition comprising a compound as defined in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

23. A compound as defined in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 22: (i) for therapeutic purposes; (ii) treatment of cancer; (iii) treating 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); (iv) Treatment of triplet repeat disorders.

24. A method of treating cancer or a triplet repeat disorder in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 22.

25. A method for treating cancer according to claim 24, wherein the method comprises administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 22, 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).

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