(Hetero)aryl-carbonyl-heterobicyclic compounds as PMS2 inhibitors for cancer and degenerative diseases

Abstract

The present invention relates to compounds of formula (I) that target the PMS2 protein, a component of the DNA mismatch repair (MMR) process 【Chemical 1】 JPEG2026520460000525.jpg46170(wherein R 2 , R 3 , R 4 , R 5 , X, Y 1 , Y 2 , A 1 , A 2 , A 3 and A 4 and all groups related thereto are as defined herein respectively). The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders such as cancer and other diseases or conditions in which PMS2 activity is involved.

Description

[Technical Field]

[0001] This invention relates to specific compounds that function as inhibitors of PMS2 protein activity. In particular, the compounds of this invention can be used as covalent agents for inhibiting PMS2. Therefore, the compounds of this invention can be used to treat diseases or conditions that are at least partially mediated by inappropriate PMS2 activity, such as cancer. This invention further relates to the use of compounds and pharmaceutical compositions containing them. [Background technology]

[0002] Cancer is caused by altered cell proliferation. For decades, intense research has focused on precisely what causes cells to become malignant and proliferate uncontrollably. This research has led to the identification of molecular targets associated with the major pathways that give rise to such malignant tumors.

[0003] Mismatch repair (MMR) is a highly conserved DNA repair pathway that plays a crucial role during DNA replication, repair, and recombination, as well as during eukaryotic meiosis and mammalian immunoglobulin maturation / diversification. MMR promotes genomic stability throughout organisms by correcting DNA base mismatches and insertion / deletion (indel) loops that can occasionally occur during the normal DNA replication process. Base pair mismatches occur when incorrect nucleotides are inserted into the nascent DNA strand and escape the proofreading function of DNA polymerase. Indel loops typically occur in association with microsatellites, which are highly diverse short repeat DNA sequences distributed across both prokaryotic and eukaryotic genomes. Typically, in microsatellites, the template and primer strands are prone to slipping (dissociation and re-annealing) during replication, which can generate loop structures and a mismatched number of repeating units between the template and nascent strands.

[0004] DNA mismatch repair is a bidirectional excision and resynthesis system that begins with a defined 3'- or 5'- strand break for a mismatch. The excision region extends just past the mismatch. MMR can be divided into four steps: 1) mismatch recognition by MSH proteins, 2) recruitment of MLH / PMS proteins to link the mismatch recognition signal to the site where the distant DNA strand excision begins, 3) excision of the incorrect 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 a mismatch site triggers the recruitment of MutLα (MLH1-PMS2), forming a ternary complex in which protein-protein, protein-DNA interactions, and endonuclease activity 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 may also activate the latent endonuclease activity of eukaryotic MutLα proteins. After DNA cleavage, exonuclease 1 (EXO1) is recruited to excise the nascent DNA strand, and the DNA excision gap is resynthesized by DNA polymerase δ (Polδ). Once DNA resynthesis is complete, the remaining breaks are joined by DNA ligases, restoring double-strand integrity [2]. Consistent with this function, MMR is a critical tumor suppressor pathway that is lost in up to 40% of sporadic cancers. Furthermore, individuals with germline mutations in the MMR gene develop a carcinogenic state.

[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 is also characterized by an increased risk of malignancies in certain extracolonic sites, including the endometrium, ovaries, 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 for adequate MMR activity until a second hit inactivates the wild-type allele, leading to MMR deficiency.

[0006] Constitutional mismatch repair deficiency (CMMRD) syndrome is a unique childhood cancer-predisposing syndrome resulting from a single biallelic germline mutation in one of the four MMR genes: MLH1, MSH2, MSH6, or PMS2. Patients may have either homozygous biallelic changes or heterozygous changes in the MMR gene.

[0007] MMR-deficient cancers are typically characterized by a higher rate of DNA mutation accumulation than normal cells and other tumors. For example, CMMRD tumors usually have a very high mutation phenotype (>250 substitution mutations / Mb) [4]. MMR deficiency results in increased or decreased microsatellite repeat length, known as microsatellite instability (MSI). Cancers with more than 40% microsatellite variability (positive for two or more of the five microsatellite markers tested as prescribed) are described as high-frequency MSI (MSI-H). Cancers without MSI are microsatellite stable (MSS), and those with less than 40% microsatellite variability (positive for one of the five markers indicating microsatellite instability) are low-frequency MSI (MSI-L) [5]. MSI analysis is a widely used diagnostic biomarker for MMR-deficient tumors, and the MSI status is associated with a high prevalence of frameshift (FS) mutations, which can occur due to insertions / deletions within coding microsatellites. In addition to alterations in the downstream function of proteins, FS creates novel amino acid sequences that function as substrates for antigen processing and presentation[6], stimulating activation of CD8+ T cells (class I) and the “helper” function of CD4+ T cells (class II).

[0008] Cancers with a higher number of neoantigens are more susceptible to immune surveillance and more likely to respond to immunotherapy [7]. Higher neoantigen levels are associated with overall lymphocyte infiltration, TILs, memory T cells, and survival in colorectal cancer [8, 9]. This feature supports the rationale for immunotherapy-based treatment strategies [6]. Consistent with this idea, immune checkpoint inhibitors here offer a significant therapeutic advance in the treatment of MMR-deficient (MMR-d) cancer. PD-1 inhibitors, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), have been approved by the Food and Drug Administration (FDA) for patients with MMR-d or MSI-H metastatic CRC based on the significant survival benefits they provide. The CTLA-4 inhibitor ipilimumab (Yervoy) has been approved for use in combination with nivolumab for the treatment of MMR-d or MSI-H CRC patients who have been previously treated with chemotherapy. Importantly, the FDA approved the use of pembrolizumab in MMR-d / MSI-H cancer regardless of histological tumor type.

[10]

[0009] It is now recognized that clinical response to immune checkpoint inhibitors requires the presence of tumor neoantigens and infiltration of T cells that recognize such neoantigens. Higher neoantigen levels have been associated with responses to CTLA-4 and PD-1 blockade in patients with melanoma and non-small cell lung cancer [11, 12, 13]. The number of neoantigens is associated with tumor mutational load (TMB), and several large studies have confirmed that high TMB correlates with increased checkpoint inhibitor response 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 by silencing MLH1 increases TMB, resulting in a “dynamic mutation profile” and leading to persistent regeneration of neoantigens both in vitro and in vivo. This triggers immune surveillance mechanisms, resulting in control of tumor growth in mouse models, particularly in combination with immune checkpoint inhibition

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

[21] .

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

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

[23] . Overall, these reports suggest that suppression of MMR activity can lead to beneficial immune activation through activation of the cGAS-STING pathway.

[0012] MLH1 and PMS2 typically form a heterodimer. A decrease in MLH1 protein usually results in a simultaneous decrease in PMS2 protein, suggesting that either or both proteins may be essential for MMR function and cGAS / STING pathway regulation.

[0013] Therefore, there is biological and clinical evidence to highlight the need for inhibitors that target the PMS2 protein, a major component of DNA MMR, in order to reawaken the antitumor immune response.

[0014] Therefore, the present invention provides a method for treating cancer by using a small molecule as a monotherapy agent or in combination with an immunotherapy agent, another DNA damage response pathway modulator, and / or a standard therapeutic chemotherapy agent to bind to the DNA MMR component PMS2 and modulate its function.

[0015] Beyond cancer, triplet repeat diseases include over 30 human neurodegenerative and neuromuscular genetic disorders, such as Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar ataxia (SCA). Such diseases are characterized by the expansion of simple repeats in genomic DNA. These unstable repeats are typically found in different regions of several genes, and their expansion can cause disease by interfering with, for example, the expression or properties of gene products, or by affecting splicing or antisense regulation through various loss-of-function and gain-of-function pathways. Several mechanisms, including errors during DNA replication, meiotic recombination, transcription, DNA repair, and chromatin rearrangement, have been proposed to cause repeat instability, which can occur at various stages of the cell cycle. There is evidence that the functional MMR pathway is necessary to maintain the stability of microsatellite sequences. For example, Msh2- / - gene transgenic mice having a copy of human HD exon 1 (including the CAG repeat) show reduced expansion of the transfected (CAG)n repeat compared to Msh2+ / + HD exon 1 mouse controls

[24] .

[0016] Therefore, there is a need for compounds that target components of the DNA MMR process, including PMS2, to treat triplet repeat diseases. This invention was conceived with the above in mind.

[0017] References 1.Martin-Lopez, JVand R.Fishel, The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome.Fam Cancer, 2013.12(2):p.159-68. 2.Liu,D.,G.Keijzers,and L.J.Rasmussen,DNA mismatch repair and its many roles in eukaryotic cells.Mutat Res,2017.773:p.174-187. 3.Lynch,H.T.,et al.,Review of the Lynch syndrome:history,molecular genetics,screening,differential diagnosis,and medicolegal ramifications.Clin Genet,2009.76(1):p.1-18. 4.Shlien,A.,et al.,Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.Nat Genet,2015.47(3):p.257-62 5.Sehgal,R.,et al.,Lynch syndrome:an updated review.Genes(Basel),2014.5(3):p.497-507 6.Willis,J.A.,et al.,Immune Activation in Mismatch Repair-Deficient Carcinogenesis:More Than Just Mutational Rate.Clin Cancer Res,2019. 7.Gubin,M.M.and R.D.Schreiber,CANCER.The odds of immunotherapy success.Science,2015.350(6257):p.158-9. 8.Kloor,M.and M.von Knebel Doeberitz,The Immune Biology of Microsatellite-Unstable Cancer.Trends Cancer,2016.2(3):p.121-133. 9.Giannakis,M.,et al.,Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma.Cell Rep,2016.17(4):p.1206. 10.Lemery,S.,P.Keegan,and R.Pazdur,First FDA Approval Agnostic of Cancer Site-When a Biomarker Defines the Indication.N Engl J Med,2017.377(15):p.1409-1412. 11.Le,D.T.,et al.,PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.N Engl J Med,2015.372(26):p.2509-20. 12.Rizvi,N.A.,et al.,Cancer immunology.Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science,2015.348(6230):p.124-8. 13.Van Allen,E.M.,et al.,Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.Science,2015.350(6257):p.207-211. 14.Rosenberg,J.E.,et al.,Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy:a single-arm,multicentre,phase 2 trial.Lancet,2016.387(10031):p.1909-20. 15.Hellmann,M.D.,et al.,Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.Cancer Cell,2018.33(5):p.843-852 e4. 16.Rizvi,H.,et al.,Molecular Determinants of Response to Anti-Programmed Cell Death(PD)-1 and Anti-Programmed Death-Ligand 1(PD-L1)Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing.J Clin Oncol,2018.36(7):p.633-641. 17.Carbone,D.P.,et al.,First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.N Engl J Med,2017.376(25):p.2415-2426. 18.Hellmann,M.D.,et al.,Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.N Engl J Med,2018.378(22):p.2093-2104. 19.Hellmann,M.D.,et al.,Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer.Cancer Cell,2018.33(5):p.853-861 e4. 20.Germano,G.,et al.,Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth.Nature,2017.552(7683):p.116-120. 21.Mandal,R.,et al.,Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response.Science,2019.364(6439):p.485-491. 22.Guan J.,et al.,MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1 activates the cGAS-STING pathway.Cancer Cell.2021,39(1),109-121、 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. 24. Manley, K., et al., Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet, 1999.23(4):p.471-3. [Overview of the Initiative] [Means for solving the problem]

[0018] According to a first aspect of the present invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided.

[0019] A further aspect of the present invention provides a pharmaceutical composition comprising a compound defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, mixed with a pharmaceutically acceptable diluent or carrier.

[0020] A further aspect of the present invention provides a method for inhibiting PMS2 activity in vitro or in vivo, comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0021] A further aspect of the present invention provides a method for treating a PMS2 activity-related disease or disorder in a patient who requires treatment for a PMS2 activity-related disease or disorder, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0022] A further aspect of the present invention provides a method for treating a proliferative disorder in a patient requiring treatment of a proliferative disorder, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0023] A further aspect of the present invention provides a method for treating cancer in a patient requiring cancer treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0024] A further aspect of the present invention provides a method for treating triplet repeat diseases (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 patients requiring treatment of such diseases, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0025] A further aspect of 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.

[0026] A further aspect of the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use as a pharmaceutical.

[0027] A further aspect of 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 proliferative disorders.

[0028] In a further aspect of the present invention, a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, is used for the treatment of cancer. In certain embodiments, cancer is human cancer.

[0029] Further aspects of the present invention provide compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use in the treatment of triplet repeat diseases. In certain embodiments, the triplet repeat disease 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).

[0030] A further aspect of the present invention provides compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in inhibiting PMS2 activity.

[0031] A further aspect of 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 disease or disorder related to PMS2 activity.

[0032] A further aspect of the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of a pharmaceutical for the treatment of proliferative disorders.

[0033] A further aspect of the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of a pharmaceutical for the treatment of cancer.

[0034] A further aspect of the present invention provides the use of compounds defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions defined herein, in the manufacture of pharmaceuticals for the treatment of triplet repeat diseases. In certain embodiments, the triplet repeat disease 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).

[0035] A further aspect of the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of a pharmaceutical for inhibiting PMS2 activity.

[0036] A further aspect of the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of a pharmaceutical for the treatment of a disease or disorder related to PMS2 activity.

[0037] A further aspect of the present invention provides a process for preparing a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0038] Further aspects of the present invention provide compounds that can be obtained, have been obtained, or are directly obtained by a process for preparing the compounds defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0039] A further aspect of the present invention provides a novel intermediate, as defined herein, which is suitable for use in any one of the synthesis methods described herein.

[0040] In the embodiments of the present invention outlined above, the proliferative disorder is preferably cancer, and the cancer is preferably human cancer. In particular, the compounds of the present invention would be useful for the treatment of any cancer in which mismatch repair inhibition and / or cGAS / STING pathway activation are beneficial.Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendiceal cancer, astrocytoma, ataxia telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Duvet syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney complex, central nervous system tumor, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, fibrinogenic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor-GIST, germ cell tumor, Gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis / renal cell carcinoma syndrome, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prelymphoblastic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia) Hematological diseases), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin's, non-Hodgkin's), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia types 1 and 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine neoplasia (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis types 1 and 2, nevus basal cell carcinoma syndrome, oral cavity and oropharynx Cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleuroblastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi's tumor or soft tissue cancer), skin cancer, small intestine cancer, gastric cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, vulvar cancer, Waldenström macroglobulinemia, Werner syndrome, Wilms' tumor and xeroderma pigmentosum).Some interesting cancers 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 junction cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, bile duct cancer, CNS cancers, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0041] A feature comprising an optional, preferred, and desirable feature relating to one aspect of the present invention may also be a feature comprising an optional, preferred, and desirable feature relating to any other aspect of the present invention. [Modes for carrying out the invention]

[0042] definition Unless otherwise specified, the following terms used in this specification and in the claims have the meanings set forth below.

[0043] It shall be recognized that “treating” or “treatment” includes prevention and alleviation of established symptoms of a condition. Accordingly, “treating” or “treatment” of a condition, disorder or condition includes: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder or condition in a person who is susceptible to or predisposed to the condition, disorder or condition but has not experienced or shown any clinical or quasi-clinical symptoms of the condition, disorder or condition; (2) inhibiting the condition, disorder or condition, i.e., stopping, reducing or delaying the onset of the disease or its recurrence (in the case of maintenance of treatment) or at least one clinical or quasi-clinical symptom thereof; or (3) reducing or attenuating the disease, i.e., causing regression of at least one of the condition, disorder or condition or its clinical or quasi-clinical symptoms.

[0044] The "therapeutic dose" refers to the amount of a compound sufficient to achieve such treatment for a disease when administered to a mammal for the treatment of that disease. The therapeutic dose can vary depending on the compound, the disease and its severity in the mammal being treated, as well as age, weight, etc. For example, in humans or other mammals, the therapeutic dose may be determined experimentally in a research facility or clinical setting, or it may be the amount required by the guidelines of the U.S. Food and Drug Administration (FDA) or an equivalent foreign regulatory agency for the specific disease and target being treated. It should be recognized that the determination of appropriate dosage form, dose, and route of administration is within the normal level of skill in the pharmaceutical and medical fields.

[0045] Where used herein, either by itself or in conjunction with other or more terms, “subject” and “patient” refer to animals (e.g., mammals), particularly humans. Preferably, “subject” and “patient” may be non-human animals (e.g., livestock and domesticated pets) or humans.

[0046] As used herein, either by itself or in conjunction with other or more terms, “pharmaceutically acceptable” generally refers to a material that is chemically and / or physically compatible with other components (e.g., related to a formulation) and / or generally physiologically compatible with its recipient (e.g., a subject).

[0047] In this specification, the term “alkyl” refers to both linear and branched alkyl groups. References to individual alkyl groups, such as “propyl,” are specific only to linear types, and references to individual branched alkyl groups, such as “isopropyl,” are specific only to branched types. For example, (1-6C) alkyl groups include (1-4C) alkyl groups, (1-3C) alkyl groups, propyl groups, isopropyl groups, and t-butyl groups.

[0048] The term "(m~nC)" or "(m~nC) group," used alone or as a prefix, refers to any group having m to n carbon atoms.

[0049] The "alkylene" group is an alkyl group located between two other chemical groups, playing a role in linking them together. Therefore, "(1-6C)alkylene" refers to a straight-chain saturated divalent hydrocarbon group with 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group with 3 to 6 carbon atoms, such as methylene (-CH2-), ethylene isomers (-CH(CH3)- and -CH2CH2-), propylene isomers (-CH(CH3)CH2-, -CH(CH2CH3)-, -C(CH3)2- and -CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), etc.

[0050] The term "alkenyl" refers to a linear or branched alkyl group containing two or more carbon atoms, with at least one carbon-carbon double bond present within the group. Examples of alkenyl groups include ethenyl, propenyl, and buta-2,3-enyl, encompassing all possible geometric (E / Z) isomers.

[0051] The term "alkynyl" refers to linear and branched alkyl groups containing two or more carbon atoms, with at least one carbon-carbon triple bond present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0052] "(m~nC)cycloalkyl" refers to a saturated hydrocarbon ring system containing m~n carbon atoms. Exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicyclo[2.2.1]heptyl.

[0053] The term "alkoxy" refers to O-bonded linear and branched alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and butoxy.

[0054] The term "cycloalkoxy" refers to an O-bonded cycloalkyl group.

[0055] The term "haloalkyl" is used herein to refer to an alkyl group in which one or more hydrogen atoms are replaced by halogen (e.g., fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2, and -CF3.

[0056] The term "haloalkoxy" is used herein to refer to an alkoxy group in which one or more hydrogen atoms are replaced by halogen (e.g., fluorine) atoms. Examples of haloalkoxy groups include -O-CH2F, -O-CHF2, and -O-CF3.

[0057] The terms "halo," "halogen," or "halogeno" refer to fluoro, chloro, bromo, and iodine, preferably fluoro, chloro, and bromo, and more preferably fluoro and chloro.

[0058] The terms "carbocykrill," "carbocyclic," or "carbocyclic" refer to non-aromatic saturated or partially saturated monocyclic, condensed, bridged, or spirodicyclic carbon-containing ring systems. Monocyclic carbocyclics contain about 3 to 12 (preferably 3 to 7) ring atoms. Bicyclic carbocyclics contain 6 to 17 member atoms, preferably 7 to 12 member atoms within the ring. Bicyclic carbocyclic rings can be condensed, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, and spiro[3.3]heptanyl.

[0059] The terms "heterocyclyl," "heterocyclic," or "heterocyclic" refer to monocyclic, condensed, bridging, or spiro-dicyclic heterocyclic systems that are non-aromatically saturated or partially saturated. Monocyclic heterocyclics contain about 3 to 12 (preferably 3 to 7) ring atoms along with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Bicyclic heterocyclics contain 7 to 17 member atoms, preferably 7 to 12 member atoms. Bicyclic heterocyclic rings can be condensed, spiro, or bridging ring systems. Examples of heterocyclic groups include cyclic ethers, e.g., oxyranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Examples of nitrogen-containing heterocyclics include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, and tetrahydropyrazolyl. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Regarding sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Examples include tetrahydrothienyl and thiomorpholinyl in sulfoxide and sulfone forms, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. The heterocycle may contain one or two oxo (=O) or thioxo (=S) substituents. Preferred values ​​for the heterocyclyl group having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl.Certain heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclines containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As those skilled in the art will recognize, any heterocycle can be linked to another group by any suitable atom, such as a carbon or nitrogen atom. However, the references herein to piperidino or morpholino refer to piperidino-1-yl or morpholin-4-yl rings linked by ring nitrogen.

[0060] The phrase "bridged ring system" refers to a ring system in which two rings share three or more atoms, for example, in Jerry March's Advanced Organic Chemistry, 4. th See Edition, Wiley Interscience, pages 131–133, 1992. Examples of cross-linked 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.

[0061] The phrase “spironicyclic ring system” means that two ring systems share one common spirocarbon atom, i.e., a heterocycle is linked to another carbon ring or heterocycle by a single common spirocarbon 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.

[0062] As used herein, either alone or in conjunction with other or more terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 π electrons (wherein n is an integer). Aromatics should be understood to include, and encompass, ring systems containing only carbon atoms (i.e., “aryl”) and ring systems containing at least one heteroatom selected from N, O, or S (i.e., “heteroaromatic” or “heteroaryl”). Aromatic ring systems may be substituted or unsubstituted.

[0063] As used herein, either alone or in conjunction with other or more terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated π system. As used herein, non-aromatic refers to, and includes, ring systems containing only carbon atoms and ring systems containing at least one heteroatom selected from N, O, or S. Non-aromatic ring systems may be substituted or unsubstituted.

[0064] The terms "heteroaryl" or "heteroaromatic" refer to aromatic monocyclic, bicyclic, or polycyclic rings incorporating one or more heteroatoms (e.g., 1 to 4, particularly 1, 2, or 3) selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10 ring members. Heteroaryl groups can be, for example, 5 or 6-membered monocyclic rings or 9 or 10-membered bicyclic rings, e.g., bicyclic structures formed from fused 5-membered and 6-membered rings or two fused 6-membered rings. Each ring can typically contain up to about 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to 3 heteroatoms, more commonly up to 2, e.g., 1 heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or fundamentally non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including the amino group substituent of the ring, will be less than five.

[0065] Examples of heteroaryls include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazeninyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, prinyl, benzoflazanil, quinolyl, iso These include quinolyl, quinazolinil, quinoxalinil, sinnolinil, pteridinil, naphthilidinil, carbazolyl, phenadinil, benzisoquinolinil, pyridopyradinil, thieno[2,3-b]furanil, 2H-flof[3,2-b]-pyranil, 5H-pyrido[2,3-d]-o-oxazinil, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinil, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinil. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is an aromatic ring and one or more other rings are non-aromatic saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxynyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indlinyl, 1,2,3,4-tetrahydro-1,8-naphthilidinyl, 1,2,3,4-tetrahydropyrido[2,3-]pyradinyl, and 3,4-dihydro-2-pyrido[3,2-][1,4]oxazinyl.

[0066] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanil, thienyl, imidazolyl, furazanil, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0067] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0068] A bicyclic heteroaryl group can be, for example, a group selected from the following: A benzene ring condensed into a 5 or 6-membered ring containing 1, 2, or 3 ring heteroatoms, A pyridine ring condensed into a 5 or 6-membered ring containing 1, 2, or 3 ring heteroatoms, A pyrimidine ring condensed into a 5 or 6-membered ring containing one or two ring heteroatoms, A pyrrole ring condensed into a 5 or 6-membered ring containing 1, 2, or 3 ring heteroatoms, A pyrazole ring condensed into a 5 or 6-membered ring containing one or two ring heteroatoms, A pyrazine ring condensed into a 5 or 6-membered ring containing one or two ring heteroatoms, An imidazole ring condensed into a 5 or 6-membered ring containing one or two ring heteroatoms, An oxazole ring condensed to a 5 or 6-membered ring containing one or two ring heteroatoms, An isoxazole ring condensed into a 5 or 6-membered ring containing one or two ring heteroatoms, A thiazole ring condensed to a 5 or 6-membered ring containing one or two ring heteroatoms, An isothiazole ring condensed to a 5 or 6-membered ring containing one or two ring heteroatoms, A thiophene ring condensed into a 5 or 6-membered ring containing 1, 2, or 3 ring heteroatoms, A furan ring fused to a 5 or 6-membered ring containing 1, 2, or 3 ring heteroatoms, A cyclohexyl ring fused to a 5 or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms, and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms.

[0069] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzthiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolidinyl, indolinyl, isoindolinyl, prinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0070] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, clomenyl, isochromanyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzooxazinyl, benzodiadinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, synnolinyl, phthalazinyl, naphthilidinyl, and pteridinyl groups.

[0071] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent forms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In certain embodiments, aryl is phenyl.

[0072] The terms "[(m~nC)alkyl]amino" and "di-[(m~nC)alkyl]amino" refer to an amino group substituted with one or two (m~nC) alkyl groups, respectively.

[0073] This specification also uses several compound terms to describe groups containing two or more functional groups. Such terms will be understood by those skilled in the art. For example, (3-6C)cycloalkyl(m-nC)alkyl includes (m-nC)alkyl substituted with (3-6C)cycloalkyl. Similarly, hydroxy-(m-nC)alkyl, (m-nC)alkoxy-(m-nC)alkyl, cycloalkyl-(m-nC)alkyl, aryl-(m-nC)alkyl, heterocyclyl-(m-nC)alkyl and heteroaryl-(m-nC)alkyl will be understood by those skilled in the art to mean (m-nC)alkyl substituted with hydroxy, (m-nC)alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, respectively. Similarly, amino-(m~nC)alkyl, [(m~nC)alkyl]amino-(m~nC)alkyl, di-[(m~nC)alkyl]amino-(m~nC)alkyl, and [(m~nC)alkyl][(m~nC)cycloalkyl]amino-(m~nC)alkyl will be understood by those skilled in the art to mean (m~nC)alkyl substituted with amino, [(m~nC)alkyl]amino, di-[(m~nC)alkyl]amino, and [(m~nC)alkyl][(m~nC)cycloalkyl]amino, respectively.

[0074] The term "arbitrarily substituted" refers to both the substituted group, structure, or molecule and the unsubstituted group. For example, the term "R 8A Any alkyl moiety present is optionally substituted, or the term "R 8A "Any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyrillic moiety present in is optionally substituted" preferably means R 8A This means that one of the hydrogen groups of the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyrillic moiety present in the compound is substituted by the relevant defined group.

[0075] When an optional substituent is selected from "one or more" groups, this definition is to be understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. In some embodiments, one or more refers to 1, 2 or 3. In another embodiment, one or more refers to 1 or 2. In certain embodiments, one or more refers to 1.

[0076] The term "compounds of the present invention" means compounds disclosed herein, generally and specifically.

[0077] "About", as used herein in connection with a measurable value such as an amount or period, is intended to encompass reasonable variations of the value that take into account, for example, experimental error in the measurement of the value.

[0078] compound In one aspect, the present invention relates to a compound having the structural formula (I) shown below or a pharmaceutically acceptable salt, hydrate or solvate thereof: [Chemical formula] (wherein, R 2 is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl, R 3 is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy, amino-(1-6C)alkyl or (1-6C)haloalkyl, R 4 is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (1-6C)haloalkoxy or NR 4A R 4B where R 4A and R 4B are each independently selected from hydrogen or (1-6C)alkyl, R 5is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl, or R 4 and R 5 They are linked together with the atom to which they are bonded, so that they form a 4-6 member heterocycline or heteroaryl, and each 4-6 member heterocycline or heteroaryl has one or more R A It is optionally replaced by each R A This is independently selected from halo, cyano, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, or (1-6C)haloalkyl. X is N, CH, or CR 6 And R 6 These are halo, cyano, (1-6C)alkyl, or (1-6C)haloalkyl. Y 1 These are -CH2-, C(=O)-, or -CHR B And R B This is selected from halo, cyano, methyl, methoxy, CF3, -OCF3, or hydroxymethyl. Y 2 -CH2-, -C(=O)-, -CHR C -, -CH2-CH2-, -CH2-CHR C - or -CHR C -CH2- and R C This is selected from halo, cyano, methyl, methoxy, CF3, -OCF3, or hydroxymethyl. A 1 N, CH, CR 7 or CR 12 Selected from, A 2 N, CH, CR 7 or CR 12 Selected from, A 3 is N, CH, or CR 13 Selected from, A 4 is N, CH, or CR 14 Selected from, however, A1 , A 2 , A 3 Or A 4 Only one or two of these can be N, and A 1 and A 2 One of them is CR 7 And, R 7 This is represented by the following formula (IA) or (IB): [ka] It is the basis of, [ka] This indicates a connection point to A1 or A2. R 8A These are hydrogen, (1-6C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, heterocyclyl-(1-4C)alkyl, heteroaryl-(1-4C)alkyl, or 8-12 membered carbocyclyl. R 8A Each alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and each phenyl or 4-6 membered heterocyclyl is further optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy. R 8AAny alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyclyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and any phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy. R 8 This is represented by the following formula (IA-I) or (IA-II): [ka] It is the basis of, [ka] The arrow indicates a connection point. R 8B and R 8D These include hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, and -C(O)NR 8F R 8G Each is independently selected from the group consisting of R 8F and R 8G These are independently selected from hydrogen or (1-4C) alkyl groups. R 8B and / or R 8D Any alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R 8B and / or R 8DAny cycloalkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R 8C This is selected from hydrogen, halo, (1-6C)alkyl, (1-6C)alkoxy, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, di[(3-6C)cycloalkyl]amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, heterocyclyl-(1-4C)alkyl, or heteroaryl-(1-4C)alkyl. R 8C Any alkyl moiety present is a halo, hydroxy, cyano, oxo, (1-6C)alkoxy, or NR. 8CA R 8CB (Here, R 8CA and R 8CB Each is optionally substituted with one or more substituents independently selected from hydrogen and (1-6C)alkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and each phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy. R 8C Any alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present in [the specified form] is a halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, or NR moiety.8CC R 8CD (Here, R 8CC and R 8CD Each is optionally substituted with one or more substituents independently selected from hydrogen and (1-6C)alkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and each phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy, or R 8A and R 8D These atoms, along with the atoms to which they are bonded, are linked so that they form 4-6 membered heterocyclines, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclines. R 8E This is selected from the group consisting of hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, and (3-6C)cycloalkyl-(1-2C)alkyl. R 8E Any alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R 8E Any cycloalkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R 12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, (3-6C)cycloalkyl, and any of the (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted by one or more halo or (1-2C)alkoxy, or R 12 is -(CHR p ) f -Z 12 where R p is hydrogen or methyl, f 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 4-6 member heterocyclyl, 5- or 6-member heteroaryl, -(CHR q ) e -(3-7C)cycloalkyl, -(CHR q ) e -phenyl, -(CHR q ) e -[4-6 member heterocyclyl] or -(CHR q ) e -[5- or 6-member heteroaryl], R q is hydrogen or methyl, and e is 0 or 1, R 21 and R 22 are hydrogen, (1-6C)alkyl, (2-6C)alkanoyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5- or 6-member heteroaryl, -(CHR r ) d -(3-7C)cycloalkyl, -(CHR r ) d -phenyl, -(CHR r )d -[4-6 member heterocycline] or -(CHR) r ) d -[5- or 6-membered heteroaryls] are independently selected, R r is hydrogen or methyl, and d is either 0 or 1, or R 21 and R 22 They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R 23 is hydrogen or (1-2C) alkyl, R 24 (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR s ) c -(3~7C)cycloalkyl, -(CHR s ) c -phenyl, -(CHR s ) c -[4-6 member heterocycline] or -(CHR) s ) c -[5 or 6-membered heteroaryl], R s is hydrogen or methyl, and c is either 0 or 1. R 20 , R 21 , R 22 , R 23 Or R 24 Each of or R 21 and R 22 Any ring formed when they are connected contains one or more R D It is optionally replaced by, R 13is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 13 is, -(CHR o ) h -Z 13 And, R o is hydrogen or methyl, h is 0 or 1, and Z 13 is -OR 25 , -NR 26 R 27 -C(O)NR 26 R 27 or -NR 28 C(O)R 29 And, R 25 (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR n ) i -(3~7C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-6 member heterocycline] or -(CHR) n ) i -[5 or 6-membered heteroaryl], R n is hydrogen or methyl, and i is either 0 or 1. R 26 and R 27 These are hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR m ) j -(3~7C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m) j -[4-6 member heterocycline] or -(CHR) m ) j -[5- or 6-membered heteroaryls] are independently selected, R m is hydrogen or methyl, and j is either 0 or 1, or R 26 and R 27 They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R 28 is hydrogen or (1-2C) alkyl, R 29 (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR l ) k -(3~7C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-6 member heterocycline] or -(CHR) l ) k -[5 or 6-membered heteroaryl], R l is hydrogen or methyl, and k is either 0 or 1. R 25 , R 26 , R 27 , R 28 Or R 29 Each of or R 26 and R 27 Any ring formed when they are connected contains one or more R D It is optionally replaced by, R 14is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 14 ha-(CHR k ) m -Z 14 And, R k is hydrogen or methyl, 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 And, R 30 (1-4C) alkyl, (3-7C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3~7C)cycloalkyl, -(CHR j ) o -[4-6 member heterocycline] or -(CHR) j ) o -[5 or 6-membered heteroaryl], R j is hydrogen or methyl, and o is either 0 or 1. R 31 and R 32 These are hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR i ) p -(3~7C)cycloalkyl, -(CHR i ) p -[4-6 member heterocycline] or -(CHR) i ) p-[5- or 6-membered heteroaryls] are independently selected, R i is hydrogen or methyl, and p is either 0 or 1, or R 31 and R 32 They are linked together with the nitrogen atoms to which they are bonded, so that they form a 4-6 membered heterocycle. R 33 is hydrogen or (1-2C) alkyl, R 34 (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR h ) q -(3~7C)cycloalkyl, -(CHR h ) q -[4-6 member heterocycline] or -(CHR) h ) q -[5 or 6-membered heteroaryl], R h is hydrogen or methyl, and q is either 0 or 1, R 30 , R 31 , R 32 , R 33 Or R 34 Each of or R 31 and R 32 Any ring formed when they are connected contains one or more R D It is optionally replaced by, Each R D These are oxo, halo, cyano, hydroxy, (1-4C) alkyl or group: -L 1 -X 1 -Q 1 (In the formula, L 1 It does not exist, or it is an (1-2C) alkylene. X 1 It does not exist, or -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O)0-2 -, -C(O)-N(R 15 )-,-N(R 15 )-C(O)-, -NR 15 -, -N(R 15 )-C(O)-NR 15 -, -SO2N(R 15 )- or -N(R 15 Selected from the group consisting of )SO2-, each R 15 is independently selected from hydrogen or (1-4C) alkyl, and Q 1 (Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl) (Selected independently from the group consisting of...)

[0079] In another aspect, the present invention relates to a compound having the following structural formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [ka] (In the formula, R 2 , R 5 , X, Y 1 , Y 2 , A 1 , A 2 , A 3 and A 4 As defined above, R 3 is hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl, and R 4 This refers to hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl or NR 4A R 4B And R 4A and R 4B (Each element is independently selected from hydrogen or (1-6C) alkyl groups).

[0080] Examples of specific compounds of the present invention include, unless otherwise specified, R 2 , R 3 , R 4 , R 5 , X, Y 1 , Y 2 , A 1 , A 2 , A 3 , A 4 There are compounds of formula (I) or pharmaceutically acceptable salts, hydrates, and / or solvates thereof in which each of and any group associated therewith has either the meaning defined herein or any of the meanings set out in any of paragraphs (1) to (111): (1)R 2 These are hydrogen, halo, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, or (1-4C)haloalkyl. (2)R 2 These are hydrogen, halo, hydroxy, (1-3C)alkyl, (1-3C)alkoxy, or (1-3C)haloalkyl. (3)R 2 These are hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, methoxy, ethoxy, CH2F, CHF2, or CF3. (4)R 2 is hydrogen, fluoro, chloro, hydroxy, methyl, methoxy or CHF2. (5)R 2 is hydrogen or hydroxyl. (6)R 3 These are hydrogen, halo, hydroxy, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy, amino-(1-4C)alkyl, or (1-4C)haloalkyl. (7)R 3 These are hydrogen, halo, hydroxy, (1-3C)alkyl, hydroxy-(1-3C)alkyl, (1-3C)alkoxy, amino-(1-3C)alkyl, or (1-3C)haloalkyl. (8)R 3These are hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, aminomethyl, aminoethyl, CH2F, CHF2, or CF3. (9)R 3 is hydrogen, fluoro, chloro, hydroxy, methyl, hydroxymethyl, methoxy, or aminomethyl. (10)R 3 is hydrogen or methyl, (11)R 4 This refers to hydrogen, halo, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, or NR. 4A R 4B And R 4A and R 4B These are independently selected from hydrogen or (1-4C) alkyl groups. (12)R 4 This refers to hydrogen, halo, hydroxy, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (1-3C)haloalkoxy or NR 4A R 4B And R 4A and R 4B These are independently selected from hydrogen or (1-3C) alkyl groups. (13)R 4 This refers to hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, CH2F, CHF2, CF3, O-CH2F, O-CHF2, O-CF3, or NR. 4A R 4B And R 4A and R 4B is independently selected from hydrogen, methyl, or ethyl. (14)R 4 These are hydrogen, fluoro, hydroxy, methoxy, CHF2, O-CHF2, or NH2. (15)R 4 is hydrogen, hydroxyl, or methoxy. (16)R 5 These are hydrogen, halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, or (1-4C)haloalkyl. (17)R 5 These are hydrogen, halo, cyano, hydroxy, (1-3C)alkyl, (1-3C)alkoxy, or (1-3C)haloalkyl. (18)R 5 These are hydrogen, fluoro, chloro, bromo, cyano, hydroxy, methyl, ethyl, propyl (e.g., n-propyl or i-propyl), butyl (e.g., n-butyl, i-butyl or t-butyl), methoxy, ethoxy, CH2F, CHF2, or CF3. (19)R 5 These are hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl (e.g., n-propyl or i-propyl), butyl (e.g., n-butyl, i-butyl or t-butyl), methoxy, or CF3. (20)R 5 is hydrogen, chloro, methyl, propyl (e.g., i-propyl), butyl (e.g., t-butyl), or CF3. (21)R 4 and R 5 They are linked together with the atom to which they are bonded, so that they form a 5-6 member heterocycline or 5-6 member heteroaryl, and each 5-6 member heterocycline or 5-6 member heteroaryl has 1, 2, or 3 R A It is optionally replaced by (22)R 4 and R 5 They are linked together with the atoms to which they are bonded, so as to form a 5-6 member nitrogen- or oxygen-containing heterocycline or a 5-6 member nitrogen- or oxygen-containing heteroaryl, and each 5-6 member nitrogen- or oxygen-containing heterocycline or 5-6 member nitrogen- or oxygen-containing heteroaryl has 1, 2, or 3 R A It is optionally replaced by (23)R 4 and R 5They are linked together with the atom to which they are bonded, so that they form a 5-membered nitrogen-containing heterocycline or 5-membered nitrogen-containing heteroaryl, and each 5-membered nitrogen-containing heterocycline or 5-membered nitrogen-containing heteroaryl has 1, 2, or 3 R A It is optionally replaced by (24)R 4 and R 5 They are linked together with the atom to which they are bonded, so that they form a five-membered heterocycline or a five-membered heteroaryl containing one or two nitrogen atoms, and each five-membered heterocycline or five-membered heteroaryl contains one, two or three R A It is optionally replaced by (25)R 4 and R 5 They are linked together with the atom to which they are bonded, so as to form a pyrrolidine ring, isoxazole ring, dihydroisoxazole ring, pyrrole ring, dihydropyrrole ring, pyrazole ring, or dihydropyrazole ring, each having 1, 2, or 3 R A It is optionally replaced by (26)R 4 and R 5 They are linked together with the atom to which they are bonded, so as to form a pyrrolidine ring, a dihydroisoxazole ring, a dihydropyrrole ring, or a dihydropyrazole ring, each of which has 1, 2, or 3 R A It is optionally replaced by [another term]. (27)R 4 and R 5 They are linked together with the atoms to which they are bonded, so as to form a ring selected from the following: [ka] (In the formula, [ka] R 4 and R 5It shows a bond that separates the carbon atom to which it is bonded, R A (as defined elsewhere in this specification), (28)Each R A This is independently selected from halo, cyano, hydroxy, oxo, (1-4C)alkyl, (1-4C)alkoxy, or (1-4C)haloalkyl. (29)Each R A This is independently selected from fluoro, chloro, bromo, hydroxy, oxo, (1-3C)alkyl, (1-3C)alkoxy, or (1-3C)haloalkyl. (30)Each R A is independently selected from fluoro, chloro, bromo, hydroxy, oxo, methyl, ethyl, methoxy, or ethoxy. (31)Each R A is independently selected from fluoro, chloro, hydroxy, oxo, methyl, or ethyl. (32)Each R A These are independently oxo or methyl. (33)X is N, CH or CR 6 And R 6 These are halo, cyano, (1-4C)alkyl, or (1-4C)haloalkyl. (34)X is N, CH or CR 6 And R 6 These are fluoro, chloro, bromo, cyano, (1-3C) alkyl, or (1-3C) haloalkyl. (35)X is N, CH, C-Cl, CF, C-Br, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, or C-CF3. (36)X is N, CH, C-Cl, CF, C-CN, C-CH3, C-CHF2, or C-CF3. (37)Y 1 These are -CH2-, C(=O)-, or -CHR B And R B is selected from fluoro, chloro, bromo, methyl, methoxy, or hydroxymethyl, (38)Y 1 is -CH2- or C(=O)-. (39)Y 1 It is -CH2- (40)Y 2 -CH2-, -C(=O)-, -CHR C -, -CH2-CH2-, -CH2-CHR C - or -CHR C -CH2- and R C is selected from fluoro, chloro, bromo, methyl, methoxy, or hydroxymethyl, (41)Y 2 These are -CH2-, -C(=O)-, or -CH2-CH2-. (42)Y 2 is -CH2- or -CH2-CH2- (43)Y 1 is -CH2- and / or Y 2 It is -CH2- or -CH2-CH2-. (44)A 1 N, CH, CR 7 or CR 12 Selected from, A 2 N, CH, CR 7 or CR 12 Selected from, A 3 is N, CH, or CR 13 Selected from, A 4 is N, CH, or CR 14 Selected from, however, A 1 , A 2 , A 3 Or A 4 Only one of them can be N, A 1 and A 2 One of them is CR 7 And, A 4 CR 14 If A 3 CR 13 It is not possible, and A 3 CR 13 If A 4CR 14 That's impossible. (45)A 1 CH, CR 7 or CR 12 Selected from, A 2 CH, CR 7 or CR 12 Selected from, A 3 is N, CH, or CR 13 Selected from, A 4 is N, CH, or CR 14 Selected from, however, A 1 , A 2 , A 3 Or A 4 Only one of them can be N, A 1 and A 2 One of them is CR 7 And, A 4 CR 14 If A 3 CR 13 It is not possible, and A 3 CR 13 If A 4 CR 14 That's impossible. (46)A 1 CH or CR 7 Selected from, A 2 CH, CR 7 or CR 12 Selected from, A 3 CH or CR 13 Selected from, A 4 CH or CR 14 Selected from, however, A 1 and A 2 One of them is CR 7 And, A 4 CR 14 If A3 CR 13 It is not possible, and A 3 CR 13 If A 4 CR 14 That's impossible. (47)A 1 CR 7 And, A 2 CH or CR 12 Selected from, A 3 CH or CR 13 Selected from, A 4 CH or CR 14 Selected from, however, A 4 CR 14 If A 3 CR 13 It is not possible, and A 3 CR 13 If A 4 CR 14 That's impossible. (48)A 1 CR 7 That is, A 2 CH or CR 12 Selected from, A 3 CH or CR 13 Selected from, A 4 CH or CR 14 Selected from, however, A 4 CR 14 If A 3 CR 13 That is impossible, A 3 CR 13 If A 4 CR 14 It is not possible, and A 3 and A 4 A2 CR 12 It is possible. (49)A 1 CR 7 That is, A 2 CH or CR 12 Selected from, A 3 CH is A 4 CH is (50)A 1 CR 7 That is, A 2 CH is A 3 CH or CR 13 That is, A 4 CH is (51)A 1 CR 7 That is, A 2 CH is A 3 CH is A 4 CH or CR 14 Selected from, (52)A 1 CR 7 That is, A 2 CH is A 3 CH is A 4 CH is (53)A 1 CH or CR 12 And, A 2 CR 7 And, A 3 CH or CR 13 Selected from, A 4 CH or CR 14 Selected from, however, A 4 CR 14 If A 3CR 13 It is not possible, and A 3 CR 13 If A 4 CR 14 That's impossible. (54)A 1 is CH or CR 12 And, A 2 CR 7 And, A 3 CH or CR 13 Selected from, A 4 CH or CR 14 Selected from, however, A 4 CR 14 If A 3 CR 13 That is impossible, A 3 CR 13 If A 4 CR 14 It is not possible, and A 3 and A 4 A 1 CR 12 It is possible. (55)A 1 CH or CR 12 That is, A 2 CR 7 That is, A 3 CH is A 4 CH is (56)A 1 CH is A 2 CR 7 That is, A 3 CH or CR 13 Selected from, A 4 CH is (57)A 1 CH is A2 CR 7 That is, A 3 CH is A 4 CH or CR 14 Selected from, (58)A 1 CH is A 2 CR 7 That is, A 3 CH is A 4 CH is (59)R 7 This is represented by the following equation (IA): [ka] (In the formula, [ka] (This indicates a connection point to A1 or A2.) The basis of, (60)R 7 This is represented by the following formula (IB): [ka] (In the formula, [ka] (This indicates a connection point to A1 or A2.) The basis of, (61)R 8A These are hydrogen, (1-4C)alkyl, hydroxy-(1-2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4-6 member cycloalkyl, aryl, 4-6 member heterocyclyl, heteroaryl, 4-6 member cycloalkyl-(1-2C)alkyl, aryl-(1-2C)alkyl, 4-6 member heterocyclyl-(1-2C)alkyl, heteroaryl-(1-2C)alkyl, or 8-10 member carbocyryl. R 8AEach alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. R 8A Any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyclyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. (62)R 8A These are hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxymethyl, hydroxyethyl, methoxymethane, methoxyethane, 5 or 6-membered cycloalkyl, phenyl, 5 or 6-membered nitrogen-containing heterocycline, 5 or 6-membered oxygen-containing heterocycline, 5 or 6-membered nitrogen-containing heteroaryl, 5 or 6-membered oxygen-containing heteroaryl, 5 or 6-membered cycloalkyl-(1-2C)alkyl, phenyl-(1-2C)alkyl, 5 or 6-membered nitrogen-containing heterocycline-(1-2C)alkyl, 5 or 6-membered oxygen-containing heterocycline-(1-2C)alkyl, 5 or 6-membered nitrogen-containing heteroaryl-(1-2C)alkyl, 5 or 6-membered oxygen-containing heteroaryl-(1-2C)alkyl, or 8-10-membered carbocycline. R 8A Any alkyl moiety present is optionally substituted with one or two substituents independently selected from chloro, fluoro, hydroxy, cyano, oxo, methoxy, ethoxy, (5-6C) cycloalkoxy, phenyl, or 5-6 member heterocyclyl. R 8AAny alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyrillic moiety present is optionally substituted with one or two substituents independently selected from chloro, fluoro, hydroxy, cyano, oxo, methyl, ethyl, methoxy, ethoxy, CHF2, CF3, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. (63)R 8A These are hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxyethyl, methoxyethane, phenyl, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1-2C)alkyl, pyridine-(1-2C)alkyl, morpholine-(1-2C)alkyl, tetrahydropyran-(1-2C)alkyl, or dihydroindene. R 8A Each alkyl moiety present is optionally substituted with one substituent selected from chloro, fluoro, hydroxy, methoxy, or phenyl. R 8A Any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyclyl moiety present is optionally substituted with one substituent selected from chloro, fluoro, hydroxy, methyl, methoxy, or phenyl. (64)R 8A These are hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxyethyl, methoxyethane, phenyl, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1-2C)alkyl, pyridine-(1-2C)alkyl, morpholine-(1-2C)alkyl, tetrahydropyran-(1-2C)alkyl, or dihydroindene. R 8A Any heterocyclyl or heteroaryl moiety present is optionally substituted with methyl. (65)R 8AThese are hydrogen, methyl, ethyl, hydroxyethyl, methoxyethane, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1C)alkyl, pyridine-(1-2C)alkyl, morpholine-(2C)alkyl, tetrahydropyran-(2C)alkyl, or dihydroindene. R 8A Any heterocyclyl or heteroaryl moiety present is optionally substituted with methyl. (66)R 8 This is represented by the following equation (IA-I): [ka] (In the formula, [ka] (This indicates a connection point.) The basis of, (67)R 8B and R 8D These include hydrogen, halo, (1-2C)alkyl, (4-6C)cycloalkyl, (4-6C)cycloalkyl-(1-2C)alkyl, and -C(O)NR 8F R 8G Each is independently selected from the group consisting of R 8F and R 8G These are independently selected from hydrogen or (1-2C) alkyl, R 8B and / or R 8D Each alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. R 8B and / or R 8DAny cycloalkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. (68)R 8B and R 8D These are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, and -C(O)NH2, R 8B and / or R 8D Any alkyl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, methoxy, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. R 8B and / or R 8D Any cycloalkyl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, methyl, methoxy, CH2F, CF3, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. (69)R 8B and R 8D These are independently selected from the group consisting of hydrogen, fluoro, chloro, or methyl. (70)R 8B and R 8D Both are hydrogen. (71)R 8 This is represented by the following equation (IA-Ia): [ka] (In the formula, [ka] (This indicates a connection point.) The basis of, (72)R 8CThis is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, 4-6 member cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, 4-6 member heterocyclyl-(1-4C)alkyl, or heteroaryl-(1-4C)alkyl. R 8C Any alkyl moiety present is a halo, hydroxy, cyano, oxo, (1-3C)alkoxy, or NR. 8CA R 8CB (Here, R 8CA and R 8CB Each is optionally substituted with one or more substituents independently selected from hydrogen and (1-3C)alkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl, and each phenyl or 5-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4-6C)cycloalkyl, or (4-6C)cycloalkoxy. R 8C Any alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present in [the specified form] is a halo, hydroxy, cyano, oxo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, or NR moiety. 8CC R 8CD (Here, R 8CC and R 8CDEach molecule is optionally substituted with one or more substituents independently selected from hydrogen and (1-4C)alkyl groups, (4-6C)cycloalkoxy groups, phenyl groups, or 5-6 member heterocyclines, and each phenyl group or 5-6 member heterocycline is optionally further substituted with one or more substituents independently selected from halo, hydroxyl, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4-6C)cycloalkyl, or (4-6C)cycloalkoxy groups. (73)R 8C This is selected from hydrogen, fluoro, chloro, bromo, (1-3C)alkyl, (1-3C)alkoxy, [(1-3C)alkyl]amino, di-[(1-3C)alkyl]amino, amino-(1-3C)alkyl, [(1-3C)alkyl]amino-(1-3C)alkyl, di-[(1-3C)alkyl]amino-(1-3C)alkyl, [(1-3C)alkyl][(3-5C)cycloalkyl]amino-(1-3C)alkyl, hydroxy-(1-3C)alkyl, (1-3C)alkoxy-(1-3C)alkyl, 4-6 member cycloalkyl-(1-3C)alkyl, aryl-(1-3C)alkyl, 4-6 member heterocyclyl-(1-3C)alkyl, or heteroaryl-(1-3C)alkyl. R 8C Each alkyl moiety present is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkoxy, NH2, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl, and each phenyl or 5-6 membered heterocyclyl is further optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl, or methoxy. R 8CAny alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, NH2, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl, and any phenyl or 5-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl, or methoxy. (74)R 8C This is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, [(1~2C)alkyl]amino, di-[(1~2C)alkyl]amino, amino-(1~2C)alkyl, [(1~2C)alkyl]amino-(1~2C)alkyl, di-[(1~2C)alkyl]amino-(1~2C)alkyl, [(1~2C)alkyl][(3~4C)cycloalkyl]amino-(1~2C)alkyl, hydroxy-(1~2C)alkyl, (1~2C)alkoxy-(1~2C)alkyl, 4~6 member cycloalkyl-(1~2C)alkyl, aryl-(1~2C)alkyl, 4~6 member nitrogen-containing heterocyclyl-(1~2C)alkyl, or nitrogen-containing heteroaryl-(1~2C)alkyl. R 8C Any alkyl moiety present is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methoxy, NH2, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. R 8C Any alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, NH2, (5-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. (75)R 8CThis is selected from hydrogen, methyl, methoxy, [(1~2C)alkyl]amino, di-[(1~2C)alkyl]amino, amino-(1~2C)alkyl, [(1~2C)alkyl]amino-(1~2C)alkyl, di-[(1~2C)alkyl]amino-(1~2C)alkyl, [(1~2C)alkyl][(3~4C)cycloalkyl]amino-(1~2C)alkyl, (1~2C)alkoxy-(1~2C)alkyl, 4~6 member cycloalkyl-(1~2C)alkyl, phenyl-(1~2C)alkyl, 4~6 member nitrogen-containing heterocyclyl-(1~2C)alkyl, or nitrogen-containing heteroaryl-(1~2C)alkyl. R 8C Any alkyl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy, or NH2. R 8C Any alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, cyano, oxo, methyl, methoxy, CHF2, CF3, or NH2. (76)R 8C This is selected from hydrogen, methyl, [(1~2C)alkyl]amino, di-[(1~2C)alkyl]amino, amino-(1~2C)alkyl, [(1~2C)alkyl]amino-(1~2C)alkyl, di-[(1~2C)alkyl]amino-(1~2C)alkyl, [(1~2C)alkyl][(3~4C)cycloalkyl]amino-(1~2C)alkyl, (1~2C)alkoxy-(1~2C)alkyl, 4~6 member nitrogen-containing heterocyclyl-(1~2C)alkyl, or nitrogen-containing heteroaryl-(1~2C)alkyl. R 8C Any alkyl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy, or NH2. R 8CAny alkoxy, heterocyclyl, or heteroaryl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy, or NH2. (77)R 8c It is hydrogen, methyl, -CH2-NR 8C1 R 8C2 -CH2-N(R 8C1 )(3C)cycloalkyl, NR 8C1 R 8C2 Selected from (1-2C)alkoxy-(1-2C)alkyl, 4-6 member nitrogen-containing heterocyclyl-(1-2C)alkyl, or nitrogen-containing heteroaryl-(1-2C)alkyl, R 8C1 and R 8C2 These are independently selected from hydrogen, methyl, and ethyl. R 8C Any alkyl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methoxy, or NH2. R 8C Any alkoxy, heterocyclyl, or heteroaryl moiety present is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy, or NH2. (78)R 8c This is selected from hydrogen, methyl, -CH2-NH2, -CH2-NMe2, -CH2-Net2, -CH2-N(Me)Et, CH2-N(Me)cyclopropyl, -NH2, -Nme2, (1~2C)alkoxy-(1~2C)alkyl, pyrrolidine-(1~2C)alkyl, morpholine-(1~2C)alkyl, or azetidine-(1~2C)alkyl. R 8C Any alkoxy, heterocyclyl, or heteroaryl moiety present is optionally substituted with two substituents independently selected from fluoro, chloro, hydroxy, or methyl. (79)R 8cThis is selected from hydrogen, methyl, -CH2-Nme2, -CH2-N(Me)Et, methoxymethane, pyrrolidine-(1C)alkyl, morpholine-(1C)alkyl, or azetidine-(1C)alkyl. R 8C Any alkoxy, heterocyclyl, or heteroaryl moiety present is optionally substituted with two substituents independently selected from fluoro or methyl. (80)R 8c This is selected from hydrogen, methyl, -CH2-Nme2, -CH2-N(Me)Et, methoxymethane, pyrrolidine-(1C)alkyl, morpholine-(1C)alkyl, or azetidine-(1C)alkyl. R 8C Each heterocyclyl moiety present is optionally substituted by two fluoropolymers. (81)R 8A and R 8D They are linked together with the atoms to which they are bonded, so that they form a 5-6 member heterocycline. Each 5-6 member heterocyclyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 member heterocyclyls. (82)R 8A and R 8D They are linked together with the atoms to which they are bonded, so that they form a 5-membered heterocycline. Each five-membered heterocyclyl is optionally substituted with one or two substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy, CHF2, or CF3, C. (83)R 8A and R 8D They are linked together with the atoms to which they are bonded, so that they form a 5-membered heterocycline. (84)R 8A and R 8DThey are linked together with the atoms to which they are bonded, so as to form pyrrolidones. (85)R 12 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 12 ha-(CHR p ) f -Z 12 And, R p is hydrogen or methyl, f 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 And, R 20 (1-3C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR q ) e -(3~6C)cycloalkyl, -(CHR q ) e -phenyl, -(CHR q ) e -[4-6 member heterocycline] or -(CHR) q ) e -[5 or 6-membered heteroaryl], R q is hydrogen or methyl, and e is either 0 or 1. R 21 and R 22 These are hydrogen, (1-4C) alkyl, (2-4C) alkanoyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR r )d -(3~6C)cycloalkyl, -(CHR r ) d -phenyl, -(CHR r ) d -[4-6 member heterocycline] or -(CHR) r ) d -[5- or 6-membered heteroaryls] are independently selected, R r is hydrogen or methyl, and d is either 0 or 1, or R 21 and R 22 They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R 23 is hydrogen or (1-2C) alkyl, R 24 (1-4C)alkyl, (2-4C)alkynyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR s ) c -(3~6C)cycloalkyl, -(CHR s ) c -phenyl, -(CHR s ) c -[4-6 member heterocycline] or -(CHR) s ) c -[5 or 6-membered heteroaryl], R s is hydrogen or methyl, and c is either 0 or 1. R 20 , R 21 , R 22 , R 23 Or R 24 Each of or R 21 and R 22 Each ring formed when they are connected has one or two R D It is optionally replaced by (86)R 12is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 12 ha-(CHR p ) f -Z 12 And, R p is hydrogen or methyl, f is 0 or 1, and Z 12 is -OR 20 or -NR 21 R 22 And, R 20 These are (1-3C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl. R 21 and R 22 These are independently selected from hydrogen, (1-2C) alkyl, (2-3C) alkanoyl, (4-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, or R 21 and R 22 They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R 20 , R 21 Or R 22 Each of or R 21 and R 22 Each ring formed when they are connected has one or two R D It is optionally replaced by (87)R 12 This is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, or R 12 Ha-Z 12 And, Z12 は-OR 20 And, R 20 It is (1-2C) alkyl, R 20 is 1 or 2 R D It is replaced by (88)R 12 is selected from chloro, methyl, or cyclopropyl. (89)R 12 is chloro or methyl. (90)R 13 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 13 ha-(CHR o ) h -Z 13 And, R o is hydrogen or methyl, h is 0 or 1, and Z 13 is -OR 25 , -NR 26 R 27 -C(O)NR 26 R 27 or -NR 28 C(O)R 29 And, R 25 (1-3C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR n ) i -(3~6C)cycloalkyl, -(CHR n ) i -phenyl, -(CHR n ) i -[4-6 member heterocycline] or -(CHR) n ) i -[5 or 6-membered heteroaryl], R nis hydrogen or methyl, and i is either 0 or 1. R 26 and R 27 These are hydrogen, (1-4C) alkyl, (2-4C) alkanoyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR m ) j -(3~6C)cycloalkyl, -(CHR m ) j -phenyl, -(CHR m ) j -[4-6 member heterocycline] or -(CHR) m ) j -[5- or 6-membered heteroaryls] are independently selected, R m is hydrogen or methyl, and j is either 0 or 1, or R 26 and R 27 They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R 28 is hydrogen or (1-2C) alkyl, R 29 (1-4C)alkyl, (2-4C)alkynyl, (3-6C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR l ) k -(3~6C)cycloalkyl, -(CHR l ) k -phenyl, -(CHR l ) k -[4-6 member heterocycline] or -(CHR) l ) k -[5 or 6-membered heteroaryl], R l is hydrogen or methyl, and k is either 0 or 1. R 25 , R 26 , R 27 , R 28 Or R29 Each of or R 26 and R 27 Each ring formed when they are connected has one or two R D It is optionally replaced by (91)R 13 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 13 ha-(CHR o ) h -Z 13 And, R o is hydrogen or methyl, h is 0 or 1, and Z 13 is -OR 25 or -NR 26 R 27 And, R 25 These are (1-3C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl. R 26 and R 27 These are independently selected from hydrogen, (1-2C) alkyl, (2-3C) alkanoyl, (4-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, or R 26 and R 27 They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R 25 , R 26 Or R 27 Each of or R 26 and R 27 Each ring formed when they are connected has one or two R D It is optionally replaced by (92)R 13 This is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, or R 13 Ha-Z 13 And, Z 13 は-OR 25 And, R 25 It is (1-2C) alkyl, R 25 is 1 or 2 R D It is replaced by (93)R 13 is selected from chloro, methyl, methoxy, or -O-CH2-CH2-N(Me)2. (94)R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 14 ha-(CHR k ) m -Z 14 And, R k is hydrogen or methyl, 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 And, R 30 (1-3C) alkyl, (3-6C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR j ) o -(3~6C)cycloalkyl, -(CHR j ) o -[4-6 member heterocycline] or -(CHR)j ) o -[5 or 6-membered heteroaryl], R j is hydrogen or methyl, and o is either 0 or 1. R 31 and R 32 These are hydrogen, (1-4C) alkyl, (2-4C) alkanoyl, (3-6C) cycloalkyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR i ) p -(3~6C)cycloalkyl, -(CHR i ) p -[4-6 member heterocycline] or -(CHR) i ) p -[5- or 6-membered heteroaryls] are independently selected, R i is hydrogen or methyl, and p is either 0 or 1, or R 31 and R 32 They are linked together with the nitrogen atoms to which they are bonded, so that they form a 4-6 membered heterocycle. R 33 is hydrogen or (1-2C) alkyl, R 34 (1-4C)alkyl, (2-4C)alkynyl, (3-6C)cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR h ) q -(3~6C)cycloalkyl, -(CHR h ) q -[4-6 member heterocycline] or -(CHR) h ) q -[5 or 6-membered heteroaryl], R h is hydrogen or methyl, and q is either 0 or 1, R 30 , R 31 , R 32 , R 33 Or R 34Each of or R 31 and R 32 Each ring formed when they are connected has one or two R D It is optionally replaced by (95)R 14 is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R 14 ha-(CHR k ) m -Z 14 And, R k is hydrogen or methyl, m is 0 or 1, and Z 14 is -OR 30 or -NR 31 R 32 And, R 30 These are (1-3C) alkyl, (3-6C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl. R 31 and R 32 These are independently selected from hydrogen, (1-2C) alkyl, (2-3C) alkanoyl, (3-6C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, or R 31 and R 32 They are linked together with the nitrogen atoms to which they are bonded, so that they form a 4-6 membered heterocycle. R 30 , R 31 Or R 32 Each of or R 31 and R 32 Any ring formed when they are connected is one or two R D It is optionally replaced by (96)R 14This is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, or R 14 Ha-Z 14 And, Z 14 は-OR 30 And, R 30 It is (1-2C) alkyl, R 30 is 1 or 2 R D It is replaced by (97)R 14 This is selected from chloro or -O-CH2-CH2-N(Me)2. (98)R 14 It is chloroform. (99)Each R D These are oxo, halo, cyano, hydroxy, (1-2C) alkyl or group: -L 1 -X 1 -Q 1 (In the formula, L 1 It does not exist, or it is an (1-2C) alkylene. X 1 Either they do not exist, or -O-, -C(O)-, -C(O)-O-, -S(O) 0~2 -, -C(O)-N(R 15 )-or-NR 15 - Selected from the group consisting of, each R 15 is independently selected from hydrogen or (1-2C)alkyl, and Q 1 (Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl) Independently selected from the group consisting of, (100) each R D is an oxo, chloro, fluoro, cyano, hydroxy, methyl or group: -L 1 -X 1 -Q 1 (In the formula, L 1 is absent or is methylene, X 1 is absent or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -NH- or NMe-, and Q 1 is selected from the group consisting of hydrogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl or (3-6C)cycloalkyl) independently selected from the group consisting of (101) Each R D is independently selected from the group consisting of oxo, chloro, fluoro, hydroxy, methyl, NH2, NHMe or NMe2, (102) A 1 is N, A 2 is CR<a 7 is, A 3 is CH or CR 13 [[ID=三十二]]selected from, A 4 is CH or CR 14 selected from, provided that A 4 is CR 14 in the case of, A 3 is CR 13 cannot be, and A 3 is CR 13 in the case of, A 4 is CR 14 cannot be, (103) A 1 is N, A 2 is CR 7 is,第71号 A 3 is CH or CR 13 is, A 4 is CH, (104) A<00009{21}}is N, A 2 is CR 7 is, A 3CH is A 4 CH is (105)A 1 CR 7 That is, A 2 is N, A 3 CH or CR 13 Selected from, A 4 CH or CR 14 Selected from, however, A 4 CR 14 If A 3 CR 13 That is not possible, and A 3 CR 13 If A 4 CR 14 That's impossible. (106)A 1 CR 7 That is, A 2 is N, A 3 CH is A 4 CH is (107)A 1 CH, CR 7 or CR 12 Selected from, A 2 CH, CR 7 or CR 12 Selected from, A 3 is N, A 4 CH or CR 14 Selected from, however, A 1 and A 2 One of them is CR 7 That is, (108)A 1 CH is A 2 CR 7 That is, A3 is N, A 4 is CH or CR, 14 selected from (109)A 1 is CH, A 2 is CR 7 is, A 3 is N, A 4 is CH, (110)A 1 is CH, CR 7 or CR 12 selected from A 2 is CH, CR 7 or CR 12 selected from A 3 is CH or CR 13 selected from A 4 is N, however, A 1 and A 2 one of them is CR 7 is, (111)A 1 is CH, A 2 is CR 7 is, A 3 is CH or CR 13 selected from A 4 is N.

[0081] Preferably, R 2 is as defined in numbered paragraph (1). More preferably, R 2 is as defined in numbered paragraph (2). Even more preferably, R 2 is as defined in numbered paragraph (3). Still even more preferably, R 2 is as defined in numbered paragraph (4). Yet even more preferably, R 2This is as defined in numbered paragraph (5).

[0082] Preferably, R 3 This is as defined in numbered paragraph (6). More preferably, R 3 This is as defined in numbered paragraph (7). More preferably, R 3 This is as defined in numbered paragraph (8). More preferably, R 3 This is as defined in numbered paragraph (9). More preferably, R 3 This is as defined in numbered paragraph (10).

[0083] Preferably, R 4 This is as defined in numbered paragraph (11). More preferably, R 4 This is as defined in numbered paragraph (12). More preferably, R 4 This is as defined in numbered paragraph (13). More preferably, R 4 This is as defined in numbered paragraph (14). More preferably, R 4 This is as defined in numbered paragraph (15).

[0084] Preferably, R 5 This is as defined in numbered paragraph (16). More preferably, R 5 This is as defined in numbered paragraph (17). More preferably, R 5 This is as defined in numbered paragraph (18). More preferably, R 5 This is as defined in numbered paragraph (19). More preferably, R 5 This is as defined in numbered paragraph (20).

[0085] Preferably, R 4 and R 5This is as defined in numbered paragraph (21). More preferably, R 4 and R 5 This is as defined in numbered paragraph (22). More preferably, R 4 and R 5 This is as defined in numbered paragraph (23). More preferably, R 4 and R 5 This is as defined in numbered paragraph (24). More preferably, R 4 and R 5 This is as defined in numbered paragraph (25). More preferably, R 4 and R 5 This is as defined in numbered paragraph (26). More preferably, R 4 and R 5 This is as defined in numbered paragraph (27).

[0086] Preferably, each R A This is as defined in numbered paragraph (28). More preferably, each R A This is as defined in numbered paragraph (29). More preferably, each R A This is as defined in numbered paragraph (30). More preferably, each R A This is as defined in numbered paragraph (31). More preferably, each R A This is as defined in numbered paragraph (32).

[0087] Preferably, X is as defined in numbered paragraph (33). More preferably, X is as defined in numbered paragraph (34). Even more preferably, X is as defined in numbered paragraph (34). Even more preferably, X is as defined in numbered paragraph (35). Even more preferably, X is as defined in numbered paragraph (36).

[0088] Preferably, Y 1 This is as defined in numbered paragraph (37). More preferably, Y 1 This is as defined in numbered paragraph (38). More preferably, Y 1 This is as defined in numbered paragraph (39).

[0089] Preferably, Y 2 This is as defined in numbered paragraph (40). More preferably, Y 2 This is as defined in numbered paragraph (41). More preferably, Y 2 This is as defined in numbered paragraph (42).

[0090] Most preferably, Y 1 and Y 2 This is as defined in numbered paragraph (43).

[0091] Preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (44). More preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (45). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (46). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (47). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (48). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (49). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (50). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (51). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (52). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (53). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (54). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (55). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (56). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (57). More preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (58).

[0092] Preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (102). More preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (103). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (104).

[0093] Preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (105). More preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (106).

[0094] Preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (107). More preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (108). Even more preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (109).

[0095] Preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (110). More preferably, A1, A2, A3, and A4 are as defined in numbered paragraph (111).

[0096] Most preferably, R 7 This is as defined in numbered paragraph (59).

[0097] Preferably, R 8A This is as defined in numbered paragraph (61). More preferably, R 8A This is as defined in numbered paragraph (62). More preferably, R 8A This is as defined in numbered paragraph (63). More preferably, R 8A This is as defined in numbered paragraph (64). More preferably, R 8A This is as defined in numbered paragraph (65).

[0098] Preferably, R 8 This is as defined in numbered paragraph (66). Most preferably, R 8 This is as defined in numbered paragraph (71).

[0099] Preferably, R 8B and R 8DThis is as defined in numbered paragraph (67). More preferably, R 8B and R 8D This is as defined in numbered paragraph (68). More preferably, R 8B and R 8D This is as defined in numbered paragraph (69). More preferably, R 8B and R 8D This is as defined in numbered paragraph (70).

[0100] Preferably, R 8C This is as defined in numbered paragraph (72). More preferably, R 8C This is as defined in numbered paragraph (73). More preferably, R 8C This is as defined in numbered paragraph (74). More preferably, R 8C This is as defined in numbered paragraph (75). More preferably, R 8C This is as defined in numbered paragraph (76). More preferably, R 8C This is as defined in numbered paragraph (77). More preferably, R 8C This is as defined in numbered paragraph (78). More preferably, R 8C This is as defined in numbered paragraph (79). More preferably, R 8C This is as defined in numbered paragraph (80).

[0101] Preferably, R 8A and R 8D This is as defined in numbered paragraph (81). More preferably, R 8A and R 8D This is as defined in numbered paragraph (82). More preferably, R 8A and R 8D This is as defined in numbered paragraph (83). More preferably, R 8Aand R 8D This is as defined in numbered paragraph (84).

[0102] Preferably, R 12 This is as defined in numbered paragraph (85). More preferably, R 12 This is as defined in numbered paragraph (86). More preferably, R 12 This is as defined in numbered paragraph (87). More preferably, R 12 This is as defined in numbered paragraph (88). More preferably, R 12 This is as defined in numbered paragraph (89).

[0103] Preferably, R 13 This is as defined in numbered paragraph (90). More preferably, R 13 This is as defined in numbered paragraph (91). More preferably, R 13 This is as defined in numbered paragraph (91). More preferably, R 13 This is as defined in numbered paragraph (92). More preferably, R 13 This is as defined in numbered paragraph (93).

[0104] Preferably, R 14 This is as defined in numbered paragraph (94). More preferably, R 14 This is as defined in numbered paragraph (95). More preferably, R 14 This is as defined in numbered paragraph (96). More preferably, R 14 This is as defined in numbered paragraph (97). More preferably, R 14 This is as defined in numbered paragraph (98).

[0105] Preferably, R DThis is as defined in numbered paragraph (99). More preferably, R D This is as defined in numbered paragraph (100). More preferably, R D This is as defined in numbered paragraph (101).

[0106] In a specific group of compounds of the present invention, the compounds have a structure according to formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) (which is a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] [ka] [ka] [ka] [ka] (In the formula, R 2 , R 4 , R 5 , X, Y 1 , Y 2 , A 1 , A 2 , A 3 , A 4 , R 8 , R 8A , R 8B , R 8C and R 8D (and any related bases are defined elsewhere in this Spec., in particular in any of the earlier numbered paragraphs.)

[0107] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0108] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (4), R4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0109] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (14), R 5 This is as defined in numbered paragraph (16), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0110] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (19), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0111] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 and R 5 This is as defined in numbered paragraphs (26) or (27), R A This is as defined in numbered paragraph (28), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0112] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 and R 5 This is as defined in numbered paragraphs (26) or (27), R A This is as defined in numbered paragraph (32), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0113] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (36), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0114] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 and Y 2 This is as defined in numbered paragraph (43), A1, A2, A3 and A4 are as defined in numbered paragraph (44), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0115] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3 and A4 are defined in any one of the numbered paragraphs (49)-(52), (55)-(58), (104), (109) or (111), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0116] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0117] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (64), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0118] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (65), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0119] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (71), R 8C This is as defined in numbered paragraph (72), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0120] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (78), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0121] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5 This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (80), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0122] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), or R 4 and R 5This is as defined in numbered paragraph (21), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are as defined in numbered paragraph (44). R 7 This is as defined in numbered paragraph (59), R 8A and R 8D This is as defined in numbered paragraph (84), R 8 This is as defined in numbered paragraph (66), R 8B This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0123] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are defined in any one of the numbered paragraphs (49), (50), (51), or (52). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), R 12 This is as defined in numbered paragraph (87), R 13 This is as defined in numbered paragraph (92), R 14 This is as defined in numbered paragraph (96), R D This is as defined in numbered paragraph (100), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0124] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are defined in any one of the numbered paragraphs (55), (56), (57), or (58). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), R 12 This is as defined in numbered paragraph (87), R 13 This is as defined in numbered paragraph (92), R 14This is as defined in numbered paragraph (96), R D This is as defined in numbered paragraph (100), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0125] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (1), R 4 This is as defined in numbered paragraph (11), R 5 This is as defined in numbered paragraph (16), X is as defined in numbered paragraph (33), Y 1 This is as defined in numbered paragraph (37), Y 2 This is as defined in numbered paragraph (40), A1, A2, A3, and A4 are defined in any one of the numbered paragraphs (104), (109), or (111). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (61), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (67), R 8C This is as defined in numbered paragraph (72), R 12 This is as defined in numbered paragraph (87), R 13 This is as defined in numbered paragraph (92), R 14 This is as defined in numbered paragraph (96), R D This is as defined in numbered paragraph (100), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0126] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (3), R 4 This is as defined in numbered paragraph (12), R 5 This is as defined in numbered paragraph (18), or R 4 and R 5 This is as defined in numbered paragraph (24), X is as defined in numbered paragraph (35), Y 1 and Y 2 This is as defined in numbered paragraph (43), A1, A2, A3, and A4 are as defined in numbered paragraph (45), R 7This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (63), R 8 This is as defined in numbered paragraph (66), R 8B and R 8D This is as defined in numbered paragraph (69), R 8C This is as defined in numbered paragraph (78), R 12 This is as defined in numbered paragraph (87), R 13 This is as defined in numbered paragraph (92), R 14 This is as defined in numbered paragraph (96), R D This is as defined in numbered paragraph (100), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0127] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, if present: R 2 This is as defined in numbered paragraph (4), R 4 This is as defined in numbered paragraph (14), R 5 This is as defined in numbered paragraph (19), or R 4 and R 5This is as defined in numbered paragraph (27), R A This is as defined in numbered paragraph (32), X is as defined in numbered paragraph (36), Y 1 and Y 2 This is as defined in numbered paragraph (43), A1, A2, A3, and A4 are as defined in numbered paragraph (45), R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (65), R 8 This is as defined in numbered paragraph (71), R 8C This is as defined in numbered paragraph (80), R 12 This is as defined in numbered paragraph (88), R 13 This is as defined in numbered paragraph (93), R 14 This is as defined in numbered paragraph (97), R D This is as defined in numbered paragraph (101), and All other bases are defined in any of the numbered paragraphs previously mentioned herein.

[0128] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, R 2This is as defined in numbered paragraph (5), R 4 This is as defined in numbered paragraph (15), R 5 This is as defined in numbered paragraph (20), X is CH, Y 1 It is -CH2-, Y 2 is -CH2- or -CH2-CH2-, A1, A2, A3, and A4 are as defined in numbered paragraphs (52) or (54), R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (65), R 8 This is as defined in numbered paragraph (71), and R 8C This is as defined in numbered paragraph (80).

[0129] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, R 2 This is as defined in numbered paragraph (5), R 4 This is as defined in numbered paragraph (15), R 5 is hydrogen or methyl, X is CH, Y 1 It is -CH2-, Y 2 It is -CH2-, A1, A2, A3, and A4 are as defined in numbered paragraph (52). R 7 This is as defined in numbered paragraph (59), R 8A This is as defined in numbered paragraph (65), R 8 This is as defined in numbered paragraph (71), and R 8C It is -CH2-N(CH3)2.

[0130] In embodiments of compounds of formula (II), (I-II), (I-III), (I-IV), (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV), (I-XVI), (I-XVII), (I-XVIII), or (I-XVIV) or their pharmaceutically acceptable salts, hydrates and / or solvates, R 2 OH is R 4 OH is R 5 It is hydrogen. X is CH. Y 1 is -CH2- Y 2 is -CH2- A1, A2, A3, and A4 are as defined in numbered paragraph (52). R 7 This is as defined in numbered paragraph (59), R 8A It is methyl. R 8 This is as defined in numbered paragraph (71), and R 8C It is -CH2-N(CH3)2.

[0131] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 2 This is as defined in the numbered paragraph (3) above. Preferably, R 2 This is as defined in the numbered paragraph (4) above. More preferably, R 2 This is as defined in the numbered paragraph (5) above.

[0132] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 3 This is as defined in the numbered paragraph (9) above. Preferably, R 3 This is as defined in the numbered paragraph (10) above.

[0133] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 4 This is as defined in the numbered paragraph (13) above. Preferably, R 4 This is as defined in the numbered paragraph (14) above. More preferably, R 4 This is as defined in the numbered paragraph (15) above.

[0134] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 5This is as defined in the numbered paragraph (19) above. Preferably, R 5 This is as defined in the numbered paragraph (20) above.

[0135] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 4 and R 5 This is as defined in the numbered paragraph (25) above. Preferably, R 4 and R 5 This is as defined in the numbered paragraphs (26) or (27) above. In either of these embodiments, R A This is as defined in the numbered paragraph (30) above.

[0136] In embodiments of any compound of formula I or any suitable sub-definitions of formula I (defined by formulas (II) to (I-XVIV)) or embodiments of any pharmaceutically acceptable salt, hydrate and / or solvate thereof described in relation to formulas (II) to (I-XVIV), X is as defined in the above numbered paragraph (35). Preferably, X is as defined in the above numbered paragraph (36).

[0137] In embodiments of any compound of formula I or any appropriate sub-definition of formula I (defined by formulas (II) to (I-XVIV)) or any embodiment described in relation to formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, Y 1 and Y 2 This is as defined in the numbered paragraph (43) above.

[0138] In embodiments of any compound of formula I or any suitable sub-definitions of formula I (defined by formulas (II) to (I-XVIV)) or embodiments of any pharmaceutically acceptable salt, hydrate and / or solvate thereof described in relation to formulas (II) to (I-XVIV), A1, A2, A3 and A4 are as defined in the above numbered paragraphs (48) or (54). Preferably, A1, A2, A3 and A4 are as defined in the above numbered paragraphs (52) or (58). Preferably, A1, A2, A3 and A4 are as defined in the above numbered paragraphs (104), (109) or (111).

[0139] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 7 This is as defined in the numbered paragraph (59) above.

[0140] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 8A This is as defined in the numbered paragraph (64) above. Preferably, R 8A This is as defined in the numbered paragraph (65) above.

[0141] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 8 This is as defined in the numbered paragraph (66) above. Preferably, R 8 This is as defined in the numbered paragraph (71) above.

[0142] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 8B and R 8D This is as defined in the numbered paragraph (69) above. Preferably, R 8B and R 8D This is as defined in the numbered paragraph (70) above.

[0143] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 8C This is as defined in the numbered paragraph (78) above. Preferably, R 8C This is as defined in the numbered paragraph (79) above. More preferably, R 8C This is as defined in the numbered paragraph (80) above.

[0144] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 8A and R 8D This is as defined in the numbered paragraph (83) above. Preferably, R 8A and R 8D This is as defined in the numbered paragraph (84) above.

[0145] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 12 This is as defined in the numbered paragraph (87) above. Preferably, R 12 This is as defined in the numbered paragraph (88) above. More preferably, R 12 This is as defined in the numbered paragraph (89) above.

[0146] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 13 This is as defined in the numbered paragraph (92) above. Preferably, R 13 This is as defined in the numbered paragraph (93) above.

[0147] In embodiments of any compound of Formula I or any appropriate sub-definition of Formula I (defined by Formulas (II) to (I-XVIV)) or any embodiment described in relation to Formulas (II) to (I-XVIV), or of a pharmaceutically acceptable salt, hydrate and / or solvate thereof, R 14 This is as defined in the numbered paragraph (96) above. Preferably, R 14 This is as defined in the numbered paragraph (97) above. More preferably, R 14 This is as defined in the numbered paragraph (98) above. In each of these embodiments, R D This is as defined in the numbered paragraph (100) above.

[0148] The specific compounds of the present invention include any of the compounds exemplified herein or their pharmaceutically acceptable salts or solvates, and in particular any of the following: (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(diethylamino)-N-((1-methyl-1H-pyrazole-4-yl)methyl)buta-2-enamide, (E)-4-(3,3-difluoropyrrolinidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, ((E)-4-(3,3-difluoroazetidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(pyrrolidine-1-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-morpholinbuta-2enamide, N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)isoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-4-fluoro-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)acrylamide, N-benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide, (E)-N-(2-(2,4-dihydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-phenethylbuta-2-enamide, (E)-N-(2-(2-chloro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3,3-dimethylindoline-5-carbonyl)isoindoline-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-hydroxyethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(pyridine-4-ylmethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-4-yl)ethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-2-yl)ethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-3-yl)ethyl)buta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-2-yl)ethyl)buta-2-enamide, E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-methoxyethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-chloro-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-1H-indole-5-carbonyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(5-bromo-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-(trifluoromethyl)benzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-cyano-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-(trifluoromethyl)benzoyl)isoindoline-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-benzoylisoindolin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-2-methoxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2-(difluoromethyl)-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2-chloro-4-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-1H-indazole-5-carbonyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(4-(difluoromethyl)-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-fluoro-2,4-dihydroxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxybenzo[d]isoxazole-5-carbonyl)isoindoline-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(4-amino-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-ethyl-2,4-dihydroxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-4-(difluoromethoxy)-6-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(4-(difluoromethoxy)-2-hydroxy-5-methylbenzoyl)isoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-(tert-butyl)-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindolin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-(trifluoromethyl)benzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-4-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-[2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl]-N-[2-(4-pyridyl)ethyl]propaneamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-N-(2-(1-methylpyrrolidine-3-yl)ethyl)acrylamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)acrylamide, N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)acrylamide, (E)-N-[2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl]-4-(dimethylamino)-N-indan-2-ylbuta-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-N-(2-morpholinoethyl)acrylamide, N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-[2-(2,4-dihydroxybenzoyl)isoindorin-4-yl]-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-fluoro-4-hydroxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-2-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-hydroxypicolinoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-methoxybenzoyl)isoindolin-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-(trifluoromethyl)benzoyl)isoindoline-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-methoxybuta-2-enamide, 1-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-3-(2-(dimethylamino)ethylidene)pyrrolidine-2-one, N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpiperidine-4-yl)acrylamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-N-(2-methoxyethyl)acrylamide, N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)-5-chloroisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)isoindoline-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(ethyl(methyl)amino)-N-methylbuta-2-enamide, (E)-N-(7-chloro-2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(7-chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(5-chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-N-ethylacrylamide, N-(2-(3-chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)isoindorin-4-yl)-N-methylacrylamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-2,3-dimethyl-1H-indole-5-carbonyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-2-methyl-1H-indole-5-carbonyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3-methyl-1H-indole-5-carbonyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-4-methoxy-5-methylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-(tert-butyl)-2-fluoro-6-hydroxy-5-(hydroxymethyl)benzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-(aminomethyl)-5-(tert-butyl)-6-fluoro-2-hydroxybenzoyl)isoindoline-4-yl)-N-methylacrylamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-5-chloroisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-ethyl-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)isoindoline-4-yl)-N-methylacrylamide, N-(2-(5-ethyl-2-hydroxy-4-methoxybenzoyl)isoindoline-4-yl)-N-methylacrylamide, (E)-N-(2-(3-(tert-butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-(tert-butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindoline-4-yl)-N-methylacrylamide, N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(5-chloro-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)isoindoline-4-yl)-N-methylacrylamide, N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridine-3-yl)-N-methylacrylamide, N-(7-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylacrylamide, N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylacrylamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-4-fluoro-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)acrylamide, (E)-N-(2-(3-chloro-6-hydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(6-(5-(tert-butyl)-2-hydroxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(5-chloro-2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-(2-(dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-inamide, (E)-N-(5-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-fluoro-4-hydroxybenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(3-chloro-2-fluoro-6-hydroxy-4-methoxybenzoyl)isoindoline-4-yl)-N-methylacrylamide, N-(5-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindoline-4-yl)-N-methylacrylamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5-methylisoindoline-4-yl)-N-methylbuta-2-enamide, N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-(2-(dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridine-3-yl)-N-methylacrylamide, (E)-N-(7-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylbuta-2-enamide, N-(7-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylacrylamide, N-(7-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylacrylamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpiperidine-4-yl)acrylamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-6-methylisoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpyrrolidine-3-yl)acrylamide, ((E)-N-(5-chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindoline-4-yl)-4-(dimethylamino)buta-2-enamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)acrylamide, (E)-N-(2-(3-chloro-6-hydroxy-2-methylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(7-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(7-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindoline-4-yl)-N-methylacrylamide, (E)-4-(dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-inamide, (E)-N-(5-chloro-2-(3-chloro-4-hydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(5-chloro-2-(4-hydroxy-2,3-dimethylbenzoyl)isoindolin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, N-(2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpiperidine-4-yl)acrylamide, (E)-4-(dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, ((E)-4-(dimethylamino)-N-(6-(4-hydroxy-3-isopropylbenzoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)buta-2-inamide.

[0149] The various functional groups and substituents constituting the compounds of formula (I) or subformulas (II) to (I-XVIV) are typically selected such that the molecular weight of the compound of formula (I) is less than 700. More generally, the molecular weight of the compound will be less than 650. More preferably, the molecular weight is less than 600.

[0150] Suitable pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonate citrate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that give pharmaceutically acceptable cations, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0151] Compounds having the same molecular formula but differing in the bonding properties or arrangement of their atoms, or in the arrangement of their atoms in space, are called "isomers." Isomers with different arrangements of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their chiral center, described by the Kahn-Prelogue R- and S- arrangement rules or by the way the molecule rotates its plane of polarization, and are indicated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as any individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0152] The compounds of the present invention may have one or more chiral centers. Therefore, such compounds may be prepared as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of specific compounds in this specification and claims is intended to include both individual enantiomers and racemic or other forms of mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by separation of racemic forms (see Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomers (E- and Z-isomers).

[0153] It should be understood that the present invention encompasses all active optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof.

[0154] The present invention also includes compounds of the present invention as defined herein that involve one or more isotopic substitutions. For example, H is1 H, 2 H(D) and 3 It can be any isotopic form containing H(T), and C is 12 C, 13 C and 14 It can be any isotopic form containing C, and O is, 16 O and 18 For example, it can be any isotopic form containing oxygen.

[0155] It should be understood that certain compounds of formula (I) or subformulas (II) to (I-XVIV) may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention encompasses all such solvated forms that are active.

[0156] It should also be understood that certain compounds of formula (I) or subformulas (II) to (I-XVIV) may exhibit polymorphism, and that the present invention encompasses all such active forms.

[0157] Compounds of formula (I) or subformulas (II) to (I-XVIV) may exist in several different tautomerized forms, and references to compounds of formula (I) or subformulas (II) to (I-XVIV) include all such forms. To avoid misunderstanding, if a compound may exist in one of several tautomerized forms and only one is specifically described or shown, then all others are nevertheless encompassed by formula (I) or subformulas (II) to (I-XVIV). Examples of tautomerized forms include, for example, the keto, enol, and enolate forms such as the following tautomerized pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acinitro. [ka]

[0158] Compounds of formula (I) or subformulas (II) to (I-XVIV) containing amine functional groups may also form N-oxides. References herein to compounds of formula (I) or subformulas (II) to (I-XVIV) containing amine functional groups also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are those of nitrogen atoms in tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides can be prepared by LWDeady's procedure, which involves reacting an amine compound with m-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane (Syn.Comm.1977,7,509-514).

[0159] Compounds of formula (I) or subformulas (II) to (I-XVIV) may be administered in the form of a prodrug that degrades in the body of a human or animal to release the compound of the present invention. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compound of the present invention. Prodrugs can be formed when the compound of the present invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed by a carboxyl group or hydroxyl group in the compound of formula (I) or subformulas (II) to (I-XVIV), and in vivo cleavable amide derivatives that can be formed by a carboxyl group or amino group in the compound of formula (I) or subformulas (II) to (I-XVIV).

[0160] Accordingly, the present invention includes compounds of formula (I) or subformulas (II) to (I-XVIV) as defined herein, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, the present invention also includes compounds of formula (I) or subformulas (II) to (I-XVIV) produced by means of organic synthesis, and such compounds produced in the body of a human or animal by the metabolism of precursor compounds of formula (I) or subformulas (II) to (I-XVIV), which may be compounds produced by synthesis or by metabolism.

[0161] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) or subformulas (II) to (I-XVIV) is one that, based on reasonable medical judgment, is free from undesirable pharmacological activity, is not excessively toxic, and is suitable for administration to the human or animal body.

[0162] Various forms of prodrugs are described in the following literature, for example: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985), b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985), c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991), d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14, and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0163] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) or subformulas (II) to (I-XVIV) having a carboxyl group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of formula (I) or subformulas (II) to (I-XVIV) containing a carboxyl group is, for example, a pharmaceutically acceptable ester that is cleaved in the body of a human or animal to produce a hydrophilic or hydrophilic alcohol. Suitable pharmaceutically acceptable esters of carboxy include (1-6C) alkyl esters, e.g., methyl, ethyl, and butyl; (1-6C) alkoxymethyl esters, e.g., methoxymethyl; (1-6C) alkanoyloxymethyl esters, e.g., pivaloyloxymethyl; 3-phthalidyl; (3-8C) cycloalkylcarbonyloxy-(1-6C) alkyl esters, e.g., cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl; 2-oxo-1,3-dioxolennylmethyl esters, e.g., 5-methyl-2-oxo-1,3-dioxolenn-4-ylmethyl; and (1-6C) alkoxycarbonyloxy-(1-6C) alkyl esters, e.g., methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl.

[0164] A suitable pharmaceutically acceptable prodrug for compounds of formula (I) or subformulas (II) to (I-XVIV) having a hydroxyl group is, for example, a cleavable ester or ether thereof. This is a pharmaceutically acceptable ester or ether having a hydroxyl group that can be cleaved in the body of a human or animal to produce a hydroxyl-parent compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including cyclic esters of phosphoramidic acids). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include (1-10C) alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and (1-10C) alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(1-6C)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(1-4C)alkylpiperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl.

[0165] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or subformulas (II) to (I-XVIV) having a carboxyl group include, for example, their amides that can be cleaved in vivo, such as amines, such as ammonia; (1-4C) alkylamines, such as methylamine; [(1-4C) alkyl] in vivo cleavable 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 amides formed with amino acids, such as glycine or its esters.

[0166] A preferred pharmaceutically acceptable prodrug of a compound having an amino group, such as a compound of formula (I) or subformulas (II) to (I-XVIV), is, for example, its amide derivatives that can be cleaved in vivo. Examples of preferred pharmaceutically acceptable amides derived from an amino group include amides formed with (1-10C) alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(1-4C)alkyl)piperazine-1-ylmethyl.

[0167] The in vivo effect of a compound of formula (I) or subformulas (II) to (I-XVIV) may be exerted in part by one or more metabolites formed in the human or animal body after administration of a compound of formula (I) or subformulas (II) to (I-XVIV). As previously stated herein, the in vivo effect of a compound of formula (I) or subformulas (II) to (I-XVIV) may also be exerted by the metabolism of a precursor compound (prodrug).

[0168] The present invention may relate to any compound or a particular group of compounds defined herein by optional, preferred or suitable features or in other respects of a particular embodiment, but the present invention may also relate to any compound or a particular group of compounds that specifically exclude the optional, preferred or suitable features or particular embodiments.

[0169] Preferably, the present invention excludes any individual compounds that do not have the biological activity defined herein.

[0170] synthesis The compounds of the present invention can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the appended examples.

[0171] In the descriptions of the synthesis methods and any referenced synthesis methods used to prepare the starting materials described herein, it should be understood that all proposed reaction conditions, including the choice of experimental solvent, reaction atmosphere, reaction temperature, duration, and workup procedures, can be selected by those skilled in the art.

[0172] Those skilled in organic synthesis will understand that the functional groups present in various parts of the molecule must be compatible with the reagents and reaction conditions used.

[0173] It will be recognized that during the synthesis of the compounds of the present invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. A skilled chemist will know when such protection is necessary and how such protecting groups can be implemented and subsequently removed.

[0174] For examples of protecting groups, please refer to one of the many general books on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any simple method described in the literature or known to a skilled chemist, as appropriate for the removal of the protecting group in question, but such methods are chosen to carry out the removal of the protecting group while minimizing interference with other groups in the molecule.

[0175] Therefore, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect those groups in some of the reactions described herein.

[0176] For example, suitable protecting groups for amino or alkylamino groups include acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with a suitable base, such as alkali metal hydroxides, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation on a catalyst such as carbon-supported palladium or by treatment with a Lewis acid, such as boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine or hydrazine.

[0177] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups like acetyl, alloyl groups, such as benzoyl, or arylmethyl groups, such as benzyl. The deprotection conditions for these protecting groups inevitably vary depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alloyl groups can be removed by hydrolysis with a suitable base such as alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl can be removed by hydrogenation on a catalyst such as carbon-supported palladium.

[0178] Suitable protecting groups for the carboxyl group are, for example, esterifying groups such as methyl or ethyl groups that can be removed by hydrolysis with a base such as sodium hydroxide, or t-butyl groups that can be removed by an acid such as an organic acid such as trifluoroacetic acid, or benzyl groups that can be removed by hydrogenation on a catalyst such as carbon-supported palladium.

[0179] Resins can also be used as protective groups.

[0180] The method used to synthesize compounds of formula (I) or subformulas (II) to (I-XVIV) is R 2 , R 3 , R 4 , R 5 , X, Y 1 , Y 2 , A 1 , A 2 , A 3 and A 4 This will also depend on the properties of any substituents or subordinate groups associated with them. Preferred processes for their preparation are further described in the attached examples.

[0181] When a compound of formula (I) or subformulas (II) to (I-XVIV) is synthesized by any one of the processes defined herein, the process may then further include the following steps: (i) Remove any existing protecting groups, (ii) Converting compound formula (I) to a compound of another formula (I), (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof, and / or (iv) To form the prodrug.

[0182] In the example of (ii) above, the compound of formula (I) is synthesized, and then the group R 2 , R 3 , R 4 , R 5 , X, Y 1 , Y 2 , A 1 , A2 , A 3 and A 4 This is the case when one or more of the groups undergo further reactions, changing the properties of the groups and providing a compound of another formula (I).

[0183] The resulting compounds of formula (I) or subformulas (II) to (I-XVIV) can be isolated and purified using techniques well known in the art.

[0184] Compounds of formula (I) or subformulas (II) to (I-XVIV) can be synthesized by the synthetic routes shown in the Examples section below.

[0185] biological activity The biological assays described in the Examples section of this specification may be used to measure the pharmacological effects of the compounds of the present invention.

[0186] As expected, the pharmacological properties of the compound of formula (I) may change with structural changes, but as described in the Examples section, the compound of the present invention was found to be active in the PMS2 in vitro assay.

[0187] Pharmaceutical composition A further aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

[0188] The compositions of the present invention may be in forms 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), external use (e.g., as creams, ointments, gels or aqueous or oily liquids or suspensions), administration by inhalation (e.g., as finely ground powders or liquid aerosols), administration by blowing (e.g., as finely ground powders), or parenteral administration (e.g., as sterile aqueous or oily liquids for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0189] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Therefore, compositions for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0190] The effective amount of the compound of the present invention for use in therapy is sufficient to prevent or treat the proliferative pathological conditions referred to herein, to slow their progression, and / or to reduce the symptoms associated with the pathological conditions.

[0191] The amount of active ingredient used to produce a single dosage form in combination with one or more excipients will inevitably vary depending on the individual being treated and the specific route of administration. For example, a formulation for oral administration to humans would generally contain 0.5 mg to 0.5 g of the active ingredient (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg) compounded with a suitable and convenient amount of excipients, which may amount to, for example, about 5 to about 98 weight percent of the total composition.

[0192] The size of the therapeutic or prophylactic dose of the compound of formula (I) will naturally vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0193] When the compounds of the present invention are used for therapeutic or preventive purposes, they will generally be administered in divided doses, if necessary, so that a daily dose of, for example, 0.1 mg / kg to 75 mg / kg body weight is received. Generally, lower doses will be administered when parenteral routes are available. For example, in intravenous or intraperitoneal administration, doses within the range, for example, 0.1 mg / kg to 30 mg / kg body weight will be commonly used. Similarly, in inhalation administration, doses within the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be particularly suitable in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compound of the present invention.

[0194] Therapeutic uses and applications The present invention provides compounds that function as inhibitors of PMS2 activity.

[0195] Therefore, compounds of formula (I) or their pharmaceutically acceptable salts have potential therapeutic applications in various pathological conditions where inhibition of PMS2 activity is beneficial.

[0196] Accordingly, the present invention provides a method for treating a disease or disorder in which inhibition of PMS2 activity is beneficial in a patient requiring treatment of such disease or disorder, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0197] The present invention provides a method for inhibiting PMS2 activity in vitro or in vivo, comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0198] The present invention provides a method for treating a proliferative disorder in a patient requiring treatment of a proliferative disorder, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0199] The present invention provides a method for treating cancer in a patient requiring cancer treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0200] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use in therapy.

[0201] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use as pharmaceuticals.

[0202] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of proliferative disorders.

[0203] The present invention provides compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use in the treatment of cancer. In certain embodiments, cancer is human cancer. In certain embodiments, cancer is human cancer, particularly estrogen-positive cancers such as breast cancer or androgen receptor-positive cancers such as prostate cancer.

[0204] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in inhibiting PMS2 activity.

[0205] The present invention provides compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of diseases or disorders in which inhibition of PMS2 activity is beneficial.

[0206] The present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, in the manufacture of pharmaceuticals for the treatment of proliferative disorders.

[0207] The present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, in the manufacture of pharmaceuticals for the treatment of cancer.

[0208] The present invention provides the use of compounds defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions defined herein, in the manufacture of pharmaceuticals for inhibiting PMS2 activity.

[0209] The present invention provides the use of compounds defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions defined herein, in the manufacture of pharmaceuticals for the treatment of diseases or disorders in which inhibition of PMS2 activity is beneficial.

[0210] The terms “proliferative disorder,” “proliferative pathology,” and “proliferative disease” are used interchangeably herein and relate to unwanted, excessive, or abnormal cell proliferation, such as neoplastic or hyperplastic growth, whether in vitro or in vivo.

[0211] In the embodiments outlined above, the proliferative disorder is preferably cancer, and the cancer is preferably human cancer. In particular, the compounds of the present invention would be useful in the treatment of any cancer in which mismatch repair inhibition is beneficial.Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma, adrenal tumors, amyloidosis, anal cancer, appendiceal cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Duvet syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney complex, central nervous system tumors, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, fibrinogenic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor-GIST, germ cell tumors, Gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis / renal cell carcinoma syndrome, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prelymphoblastic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia) Hematological diseases), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin's, non-Hodgkin's), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia types 1 and 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome (MDS), nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine neoplasia (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibromatosis types 1 and 2, nevus basal cell carcinoma syndrome, oral cavity and oropharynx Cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleuroblastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi's tumor or soft tissue cancer), skin cancer, small intestine cancer, gastric cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, vulvar cancer, Waldenström macroglobulinemia, Werner syndrome, Wilms' tumor and xeroderma pigmentosum).Specific cancers covered include hematological cancers, such as lymphoma (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemia (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 junction cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, bile duct cancer, CNS cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0212] The compounds of the present invention can also be used to treat triplet repeat disease.

[0213] Therefore, a further aspect of the present invention provides a method for treating triplet repeat diseases (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 patients requiring treatment of such triplet repeat diseases, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0214] Further aspects of the present invention provide compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use in the treatment of triplet repeat diseases. In certain embodiments, the triplet repeat disease 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).

[0215] A further aspect of the present invention provides the use of compounds defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions defined herein, in the manufacture of pharmaceuticals for the treatment of triplet repeat diseases. In certain embodiments, the triplet repeat disease 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).

[0216] Route of administration The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemically, peripherally, or externally (i.e., to the desired site of action).

[0217] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, percutaneous (e.g., including by patches, plasters, etc.), transmucosal (e.g., including by patches, plasters, etc.), intranasal (e.g., by intranasal spray), ocular (e.g., by eye drops), lung (e.g., by mouth or nose, e.g., by aerosol inhalation or inhalation therapy), rectal (e.g., by suppositories or enemas), vaginal (e.g., by pessaries), parenteral administration by injection, including intratumor, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intraarachnoid, intramedullary, intrasacral, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal, such as by implantation of subcutaneous or intramuscular depots or reservoirs.

[0218] Combination therapy The compounds of the present invention may be administered as monotherapy, or may be administered in addition to the compounds of the present invention, such as conventional surgery, radiotherapy, chemotherapy, or targeted therapy. Such chemotherapy or targeted therapy may include one or more of the following categories: (i) Antiproliferative agents / antineoplastic agents and combinations thereof used in medical oncology, for example, non-limiting alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosourea), antimetabolites (e.g., gemcitabine and antifolic acid agents, fluoropyrimidines such as 5-fluorouracil and tegafur, larcitrexed, methotrexate, cytosine arabinoside and hydroxyurea), antitumor antibiotics (e.g. For example, anthracyclines such as Adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mitramycin), antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids such as taxol and taxotere, and polokinase inhibitors), and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, camptothecin including amsacrin, topotecan, and irinotecan), (ii) Cell proliferation inhibitors, for example, not limited to, anti-estrogen drugs (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, doroxifene and iodoxifene), anti-androgen drugs (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestins (e.g., megestrol acetate) and steroid hormones including corticosteroids (e.g., dexamethasone, prednisone and prednisolone), aromatase inhibitors (e.g., anastrozole, letrozole, borazole and exemestane) and 5α-reductase inhibitors such as finasteride, (iii) Anti-infiltration agents, for example, non-limiting 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 International Publication No. 01 / 94341, Pamphlet), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydro Metalloproteinase inhibitors such as oxyethyl)piperazin-1-yl]-2-methylpyrimidine-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825, J.Med.Chem.,2004,47,6658-6661), bosutinib (SKI-606), and marimastat, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase, etc. (iv) Inhibitors of growth factor function, for example, non-limitingly, growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin®], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225] and Stern et al. (Critical reviews in Such inhibitors include any growth factor or growth factor receptor antibody disclosed in oncology / haematology, 2005, Vol. 54, pp11-29), tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, for example, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774), and 6-acrylamide-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI 1033), including 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), serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors such as farnesyltransferase inhibitors, e.g., sorafenib (BAY 43-9006), tipifarnib (R115777), and ronafarnib (SCH66336)), inhibitors of cell signaling by MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors, aurora kinase inhibitors, and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors. (v) Anti-angiogenic agents, for example, those that non-limitingly inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®) and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), batalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736) and pazopanib (GW 786034), (vi) Vascular damage agents, for example, non-limitingly, combretastatin A4 and compounds disclosed in International Patent Application Publication No. 99 / 02166, International Publication No. 00 / 40529, International Publication No. 00 / 41669, International Publication No. 01 / 92224, International Publication No. 02 / 04434 and International Publication No. 02 / 08213, (vii) Endothelin receptor antagonists, such as dibotentan (ZD4054) or atrasentan. (viii) Antisense therapies, for example, non-limited, ISIS 2503, anti-ras antisense, etc., targeting the targets listed above. (ix) Immunotherapy approaches, such as cancer vaccines, antibodies, viruses (oncolytic viruses) and small molecules, or cell therapy approaches that increase the immunogenicity of patient tumor cells and / or promote cell-mediated antitumor responses. Such therapies include, but are not limited to, OX40 agonists, cGAS-STING agonists, ENPP1 inhibitors, CD38 inhibitors, TBK1 inhibitors, A2a receptor antagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, arginase inhibitors, BTK inhibitors and bromodomain inhibitors, introduction of cancer antigens by microbial vectors, direct introduction of cancer antigens into antigen-presenting cells, therapy with cancer antigen-specific immune cells (e.g., CAR-T), and therapy with antibodies, antibody fragments and antibody-drug conjugates that enable the immune system to recognize tumor cells.

[0219] Such combination therapy may be carried out by simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination formulations utilize the compounds of the present invention and other pharmaceutically active agents within their approved dose ranges, as previously described herein.

[0220] In this aspect of the present invention, a combination is provided for use in the treatment of cancer (e.g., cancer including solid tumors), comprising the compounds of the present invention as defined herein or pharmaceutically acceptable salts or solvates thereof and an antitumor agent.

[0221] According to this aspect of the present invention, a combination is provided for use in the treatment of proliferative conditions such as cancer (e.g., cancer including solid tumors), comprising any of the compounds of the present invention as defined herein or pharmaceutically acceptable salts or solvates thereof and any of the antitumor agents listed herein earlier.

[0222] In further aspects of the present invention, compounds of the present invention or pharmaceutically acceptable salts or solvates thereof are provided for use in the treatment of cancer, optionally in combination with another antitumor agent selected from those previously listed herein.

[0223] In further aspects of the present invention, compounds of the present invention or pharmaceutically acceptable salts or solvates thereof are provided for use in the treatment of cancer in combination with a tyrosine kinase inhibitor selected from those previously listed herein.

[0224] In this specification, where the term “combination” is used, it should be understood that it refers to simultaneous, separate, or sequential administration. In one aspect of the present invention, “combination” refers to simultaneous administration. In another aspect of the present invention, “combination” refers to separate administration. In a further aspect of the present invention, “combination” refers to sequential administration. When administration is sequential or separate, any delay in administering the second component should not result in the loss of the beneficial effect of the combination.

[0225] A further aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof in combination with an antitumor agent (optionally selected from those listed earlier herein) and a pharmaceutically acceptable diluent or carrier.

[0226] Combination therapy with immunomodulatory treatment Immune checkpoint inhibitors Immune checkpoint proteins present on immune cells and / or cancer cells [e.g., CTLA4 (also known as cytotoxic T lymphocyte-associated protein 4 and CD152), LAG3 (also known as lymphocyte-activating 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 immune receptor with Ig and ITIM domains)] are molecular targets found to play a crucial role in regulating the anti-tumor immune response. Inhibitors of these immune checkpoint proteins (e.g., CTLA4, LAG3, PD1, PD-L1, TIM-3, and / or TIGIT inhibitors) can enhance the anti-tumor immune response, which can be used to effectively treat certain forms of cancer.

[0227] Immunostimulants Monoclonal antibodies, bispecific antibodies, recombinant ligands, and small molecule therapeutics that bind to stimulatory receptors on immune cells can promote effective antitumor responses. Such receptors may be involved in intercellular contact, for example, between tumor cells and immune cells or between two types of immune cells, while other receptors may bind to soluble factors that stimulate the immune response. In one such embodiment, antibodies, bispecific antibodies, recombinant proteins, or small molecule therapeutics can activate stimulatory receptors, including 4-1BB, OX40, cGAS-STING, CD27, CD40, and DR3, which enhance antitumor immunity.

[0228] Antigen processing modifiers can enhance effective antitumor responses by promoting the presentation of neoantigen peptides on the cell surface. In one such embodiment, inhibitors of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 can stimulate antitumor immunity.

[0229] In one embodiment, the present invention relates to a combination of a compound as defined herein or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor or immunostimulant as defined herein or a pharmaceutically acceptable salt thereof, for use in the treatment of proliferative disorders.

[0230] 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 immunostimulant as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of proliferative disorders.

[0231] In another embodiment, the present invention relates to a method for treating a proliferative disorder in an object requiring treatment of a proliferative disorder, comprising administering to the object a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor or immunostimulant as defined herein or a pharmaceutically acceptable salt thereof.

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

[0233] In another aspect, the present invention relates to an immune checkpoint inhibitor or immunostimulant or a pharmaceutically acceptable salt thereof for use in the treatment of proliferative disorders, wherein the immune checkpoint inhibitor is intended for simultaneous, separate, or sequential administration with a compound as defined herein or a pharmaceutically acceptable salt thereof as defined herein.

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

[0235] In another aspect, the present invention relates to the use of an immune checkpoint inhibitor or immunostimulant or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating proliferative disorders, wherein the pharmaceutical product is intended for simultaneous, separate, or sequential administration with a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0236] In another aspect, the present invention relates to a method for treating proliferative disorders, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor or immunostimulant as defined herein, or a pharmaceutically acceptable salt thereof, sequentially, separately, or simultaneously.

[0237] Any immune checkpoint inhibitor or immunostimulant may be used in combination therapies as defined herein.

[0238] 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 particular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[0239] PD-1 is a cell surface receptor protein present on immune cells such as T cells. PD-1 plays a crucial role in promoting self-tolerance by downregulating the immune system and suppressing T cell activation. The PD-1 protein is an immune checkpoint that protects against autoimmunity through a dual mechanism: it promotes apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells).

[0240] Therefore, PD-1 inhibits the immune system. This prevents autoimmune diseases, but it may also prevent the immune system from killing cancer cells.

[0241] PD-1 binds to two ligands, PD-L1 and PD-L2. PD-L1 is particularly interesting because it is highly expressed in several cancers, and therefore the role of PD-1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1, which enhances the immune system, are approved or under development for cancer treatment. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand. Inhibiting the interaction between PD-1 and PD-L1 can increase T-cell response in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.

[0242] Examples of PD-1 targeting drugs include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including cutaneous melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma. They are also being tested for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics), and MEDI-0680 (MedImmune).

[0243] Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). These drugs have also been shown to be useful for different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell carcinoma. They are also being tested for use in other types of cancer.

[0244] Examples of LAG3 inhibitors include BMS-986016 / relatrimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds to PD-1 and LAG-3), GSK2831781, and LAG525.

[0245] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab.

[0246] Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022 (Tesaro), and LY3321367 (Lilly).

[0247] Examples of TIGIT inhibitors include tiragolumab (MTIG7192A, RG6058, Genentech / Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207 (Bristol-Myers Squibb), and ASP8374 (Astellas Pharma, Potenza Therapeutics).

[0248] In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / relatrimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds to PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, MBG453, TSR-022, LY3321367, tiragolumab (MTIG7192A, RG6058), AB154, MK-7684, BMS-986207, and / or ASP8374 or a pharmaceutically acceptable salt or solvate thereof.

[0249] Combination therapy with DNA damage response modifiers The compounds of the present invention are particularly suitable for use in combination with agents that act as DNA damage response modifiers, such as PARP inhibitors, ATM inhibitors, and ATR inhibitors.

[0250] In one embodiment, the present invention relates to a combination 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, for use in the treatment of proliferative disorders.

[0251] In another aspect, the present invention relates to the use of a combination 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 in the manufacture of a pharmaceutical for treating proliferative disorders.

[0252] In another embodiment, the present invention relates to a method for treating a proliferative disorder in an object requiring treatment of a proliferative disorder, comprising administering to the object a combination comprising a compound as defined herein or a pharmaceutically acceptable salt thereof and a DNA damage response modulator (e.g., a PARP inhibitor, an ATM inhibitor and / or an ATR inhibitor) or a pharmaceutically acceptable salt thereof as defined herein.

[0253] In another aspect, the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt thereof as defined herein, for use in the treatment of proliferative disorders, wherein the compound or pharmaceutically acceptable salt thereof is intended 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.

[0254] In another aspect, the present invention relates to the use of a compound as defined herein or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a pharmaceutical product for treating proliferative disorders, wherein the pharmaceutical product is intended 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.

[0255] In another embodiment, the present invention relates to a method for treating proliferative disorders, comprising administering to a subject in need of such treatment 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, sequentially, separately, or simultaneously.

[0256] Any DNA damage response modifier (e.g., PARP inhibitors, ATM inhibitors, and / or ATR inhibitors) may be used in combination therapies as defined herein. [Examples]

[0257] Specific embodiments of the present invention have been described herein for reference and explanatory purposes, but various modifications will be apparent to those skilled in the art without departing from the scope of the invention as defined by the appended claims. Abbreviation ACN Acetonitrile Boc tert-butyloxycarbonyl Bs Broad Singlet CPME Cycopentyl Methyl Ether DAST Diethylaminosulfur Trifluoride DCM Dichloromethane Dikis bis(triphenylphosphine)palladium(II) dichloride DIPEA N,N-diisopropylethylamine, Hünig base DMA N,N-dimethylacetamide DMAP 4-(dimethylamino)pyridine DME (Dimethyl Ether) DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl ethyl acetate Et2O Diethyl ether FA Formic Acid h time HATU N-[(dimethylamino)-1-1,2,3-triazolo-[4,5-]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide HOBT N-hydroxybenzotriazole HPLC (High-Pressure Liquid Chromatography) IPA Isopropyl Alcohol LAH Lithium Aluminum Hydrogen LC-MS (Liquid Chromatography-Mass Spectrometry) MeOH methanol MI Molecular Ions min MW microwave NCS N-chlorosuccinimide NMM (N-methylmorpholine) NMR nuclear magnetic resonance PdCl2(PPh3)2-bis(triphenylphosphine)palladium chloride Pd(dppf)2Cl2[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) (Pd(dba)2) Bis(dibenzylideneacetone)palladium RT retention time or room temperature SFC Supercritical Fluid Chromatography STAB Sodium Triacetoxyborohydride TFAA Trifluoroacetic anhydride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran)

[0258] Analysis method Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash chromatography or glass column chromatography was performed using Merck silica gel with a mesh size of 230-400. Flash chromatography was also performed using a combi-flash RF Teledyne Isco machine. Preparative TLC was performed in Merck plates.

[0259] Liquid chromatography-mass spectrometry method Method A Waters Acquity UPLC with a two-component solvent manager, PDA detector, and Acquity QDA performance mass detector. Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 microns. 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 (v / v) 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. Flow rate: 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, end of run at t=4 min (97%A, 3%B), Flow rate: 0.8 mL / min, Analysis time: 4 min. Mass detector parameters: Ionization mode was cyclical between positive and negative modes with cone voltages of 10 V and 30 V and a capillary voltage of 0.8 kV, and source and probe temperatures were 120 °C and 600 °C, respectively.

[0260] Method B Waters Acquity with PDA and SQ detectors; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 microns; Column temperature: 35°C; Autosampler temperature: 5°C; Mobile phase A: 5 mM ammonium bicarbonate in water (pH=7.35); Mobile phase B: Acetonitrile; Mobile phase gradient details: t=0 min (97% A, 3% B) flow rate: 0.5 mL / min; t=0.2 min (97% A, 3% B) flow rate: 0.5 mL / min; t=2.7 min Gradient to (2%A, 98%B) flow rate: 0.5 mL / min, t=3 min. Gradient to (0%A, 100%B) flow rate: 0.7 mL / min, t=3.5 min. Gradient to (0%A, 100%B) flow rate: 0.7 mL / min, t=3.5 min. End of run at (97%A, 3%B) flow rate: 0.5 mL / min, t=4 min. Mass detector parameters: Ionization mode was cyclical in positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 3.25 kV, and source and probe temperatures were 120 °C and 400 °C, respectively.

[0261] Method C Waters Acquity UPLC with two-component solvent manager, PDA detector and Acquity QDA performance, and mass detector; Column: YMC Tri-art C18, 50×2mm, 1.9 micron; Column temperature: 35℃; Autosampler temperature: 5℃; Mobile phase A: 0.1% (v / v) formic acid in water (pH=2.70); Mobile phase B: 0.1% formic acid (v / v) in water: acetonitrile (10:90); Mobile phase gradient details: t=0 min (97%A, 3%B) flow rate: 0.8 mL / min; t=0.75 min (97%A, 3%B) flow rate: 0.8 Flow rate: 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, end of run at t=4 min (97%A, 3%B); flow rate: 0.8 mL / min; analysis time: 4 min. Mass detector parameters: Ionization mode was cycled between positive and negative modes with cone voltages of 10V and 30V and a capillary voltage of 0.8 kV, and the source and probe temperatures were 120°C and 600°C, respectively.

[0262] Method D Waters Acquity UPLC with quaternary solvent manager, PDA detector and SQ detector; Column: X-Bridge BEH C18, 50 × 2.1 mm, 2.5 microns; Column temperature: 35°C; Autosampler temperature: 5°C; Mobile phase A: 0.1% (v / v) formic acid in water (pH=2.70); Mobile phase B: 0.1% (v / v) formic acid:acetonitrile in water (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. Flow rate: 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, end of run 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 cyclically between positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 0.8 kV, source and probe temperatures were 120 °C and 400 °C, respectively.

[0263] Method E Waters Acquity UPLC with two-component solvent manager, PDA detector and Acquity QDA performance, and mass detector; Column: Welch Xtimate C18, 50 × 2.1 mm, 1.8 micron; Column temperature: 35°C; Autosampler temperature: 5°C; Mobile phase A: 0.1% (v / v) formic acid in water (pH=2.70); Mobile phase B: 0.1% formic acid (v / v) 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. Flow rate: 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, end of run at t=4 min (97%A, 3%B), Flow rate: 0.8 mL / min, Analysis time: 4 min. Mass detector parameters: Ionization mode was cyclical between positive and negative modes with cone voltages of 10 V and 30 V and a capillary voltage of 0.8 kV, and source and probe temperatures were 120 °C and 600 °C, respectively.

[0264] Method F Waters Acquity UPLC with PDA and SQ detectors, Column: Welch-Xtimate, C18 4.6×50mm, 5 microns, Column temperature: 35°C, Autosampler temperature: 5°C, Mobile phase A: 5 mM ammonium bicarbonate in water (pH=7.35), Mobile phase B: Acetonitrile, Mobile phase gradient details: t=0 min (97% A, 3% B) flow rate: 0.5 mL / min, t=0.2 min (97% A, 3% B) flow rate: 0.5 mL / min, gradient to t=2.7 min Distribution (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, end of run at t=4 min; (97%A, 3%B) flow rate: 0.5 mL / min, analysis time 4 min. Mass detector parameters: Ionization mode was cyclical between positive and negative modes with cone voltages of 10 V and 30 V and capillary voltage of 3.25 kV, and source and probe temperatures were 120 °C and 400 °C, respectively.

[0265] Method G Waters Acquity UPLC with two-component solvent manager, PDA detector and Acquity QDA performance, and mass detector; column: X-Bridge C18 2.1×50mm 3.5 micron, column temperature: 35°C, autosampler temperature: 5°C, mobile phase A: 5 mM ammonium bicarbonate in water (pH=7.35), mobile phase B: acetonitrile, mobile phase gradient details: t=0 min (97% A, 3% B) flow rate: 0.5 mL / min, t=0.2 min (97% A, 3% B) flow rate: 0.5 mL / min, gradient to t=2.7 min (2% A, 98% B) flow rate: 0.5 mL / min, gradient to t=3 min (0% A, 100% B) flow rate: 0.7 mL / min, t=3.5 min (0% A, 100% B) flow rate: 0.7 mL / min, gradient to t=3.51 min (97% A, 3% B) flow rate: 0.5 mL / min, end of run at t=4 min (97% A, 3% B), flow rate: 0.5 mL / min, analysis time 4 minutes. Mass detector parameters: The ionization mode was cycled between positive and negative modes with cone voltages of 10V and 30V and a capillary voltage of 0.8kV, and the source and probe temperatures were 120°C and 600°C, respectively.

[0266] Method H Waters 996 photodiode array detector with Waters Micromass ZQ detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 35℃, autosampler temperature: 15℃, mobile phase A: Milli Q water with 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, runtime: -17 min, UV detection method: -PDA. Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: -30 and 10V, Capillary voltage: -3.0KV, Extraction voltage: -2V, Rf lens: -0.1V, Source temperature: -120℃, Probe temperature: -400℃, Cone gas flow rate: -100L / hour, Desolvation gas flow rate: -800L / hour.

[0267] Method I Waters Acquity UPLC-H Class with PDA and QDa detector, column: X-Bridge BEH C18, 50×2.1mm, 2.5 microns, column temperature: 30℃, autosampler temperature: 15℃, mobile phase A: Milli Q 0.1% formic acid in water (pH=2.70), mobile phase B: Milli Q: 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, end of run at T=4 min (97%A, 3%B), flow rate: 0.8 mL / min, runtime: -4 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: -10V and 30V, Capillary voltage: -0.8KV, Extraction voltage: -1KV, Rf lens: -0.1, Source temperature: -120℃, Probe temperature: -600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default.

[0268] Method J Waters 996 photodiode array detector with Waters Micromass ZQ detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 60℃, autosampler temperature: 15℃, mobile phase A: Milli Q water with 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, runtime: -17 min, UV detection method: -PDA. Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: -30 and 10V, Capillary voltage: -3.0KV, Extraction voltage: -2V, Rf lens: -0.1V, Source temperature: -120℃, Probe temperature: -400℃, Cone gas flow rate: -100L / hour, Desolvation gas flow rate: -800L / hour.

[0269] Method K Agilent 1260 Infinity-II DAD detector (LC / MSD) with Agilent G6125C mass detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 35℃, autosampler temperature: 15℃, mobile phase A: Milli Q water with 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, runtime: -17 min, UV detection method: -DAD. Mass parameters: probe: MMI, ionization mode: (ESI) positive and negative, fragment voltage: -30 and 70V, capillary voltage: -3000V, source gas temperature: -325℃, vaporizer temperature: -225℃, gas flow rate: -12 L / min, nebulizer: -50

[0270] Method L Agilent 1260 Infinity-II DAD detector (LC / MSD) with Agilent G6125C mass detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 60℃, autosampler temperature: 15℃, mobile phase A: Milli Q water with 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, runtime: -17 min, UV detection method: -DAD. Mass parameters: probe: MMI, ionization mode: (ESI) positive and negative, fragment voltage: -30 and 70V, capillary voltage: -3000V, source gas temperature: -325℃, vaporizer temperature: -225℃, gas flow rate: -12 L / min, nebulizer: -50

[0271] Method M Waters 996 photodiode array detector with Waters Micromass ZQ detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 35℃, autosampler temperature: 15℃, mobile phase A: Milli Q water with 0.05% trifluoroacetic acid (pH=3.50), mobile phase B: acetonitrile. Mobile phase gradient details: T=0 min (100% A, 00% B), T=7.0 min (50% A, 50% B), gradient to T=9.0 min (00% A, 100% B), gradient to T=14.00 min (0% A, 100% B), T=14.01 min (100% A, 00% B), end of run at T=17 min (100% A, 00% B), flow rate: -1.0 mL / min, runtime: -17 min, UV detection method: -PDA. Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: -30 and 10V, Capillary voltage: -3.0KV, Extraction voltage: -2V, Rf lens: -0.1V, Source temperature: -120℃, Probe temperature: -400℃, Cone gas flow rate: -100L / hour, Desolvation gas flow rate: -800L / hour.

[0272] Method N Waters Acquity UPLC-H Class with PDA and QDa detector, column: X-Bridge BEH C18, 50×2.1mm, 2.5 microns, Column temperature: Ambient, Autosampler temperature: 15℃, Mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile, Mobile phase gradient details: T=0 min (95% A, 5% B) flow rate, T=0.4 min (95% A, 5% B), gradient to T=0.8 min (65% A, 35% B), gradient to T=1.20 min (45% A, 55% B), T=2.5 min (0% A, 100% B), gradient to T=3.30 min (0% A, 100% B), gradient to T=3.31 min, end of run at T=4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Runtime: 4 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: -default, Desolvation gas flow rate: -default.

[0273] Method O Waters Acquity UPLC-H Class with PDA and QDa detector, column: X-Bridge BEH C18, 50×2.1mm, 2.5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: Milli Q: 5 mM ammonium bicarbonate in water, mobile phase B: acetonitrile, mobile phase gradient details: flow rate at T=0 min (95% A, 5% B), gradient to T=0.4 min (95% A, 5% B), gradient to T=0.8 min (65% A, 35% B), gradient to T=1.20 min (45% A, 55% B), T=2.5 min (0% A, 100% B), gradient to T=3.30 min (0% A, 100% B), gradient to T=3.31 min, gradient to end of run at T=4 min (95% A, 5% B), flow rate: 0.55 mL / min, runtime: -4 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: -default, Desolvation gas flow rate: -default.

[0274] Method P Waters Acquity UPLC-H Class with PDA and QDa detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile, mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: 1.00 mL / min, runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0275] Method Q Waters Acquity UPLC-H Class with PDA and QDa detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile, mobile phase gradient details: T=0 min (100% A, 0% B), T=7.0 min (50% A, 50% B), gradient to T=9.0 min (0% A, 100% B), gradient to T=14.00 min (0% A, 100% B), T=14.01 min (100% A, 0% B), end of run at T=17 min (100% A, 0% B), flow rate: 1.00 mL / min, runtime: 17 minutes. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0276] Method R Waters Acquity UPLC-H Class with PDA and QDa detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile, mobile phase gradient details: T=0 min (50%A, 50%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (50%A, 50%B), end of run at T=17 min (50%A, 50%B), flow rate: 1.00 mL / min, runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: - Default, Desolvation gas flow rate: - Default.

[0277] Method S Waters Acquity UPLC-H Class with PDA and QDa detector, Column: Welch Xtimate C18, 150×4.6mm, 5 microns, Column temperature: Ambient, Autosampler temperature: 15℃, Mobile phase A: Milli Q 0.05% trifluoroacetic acid in water, Mobile phase B: Acetonitrile, Mobile phase gradient details: T=0 min (100% A, 0% B), T=7.0 min (50% A, 50% B), Gradient to T=9.0 min (0% A, 100% B), Gradient to T=14.00 min (0% A, 100% B), T=14.01 min (100% A, 0% B), End of run at T=17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: - Default, Desolvation gas flow rate: - Default.

[0278] Method T Waters Acquity UPLC with two-component solvent manager, PDA detector and Acquity QDa detector, column: X-Bridge BEH C18, 50×2.1mm, 2.5 microns, Column temperature: Ambient, Autosampler temperature: 15℃, Mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile, Mobile phase gradient details: T=0 min (95% A, 5% B) flow rate, T=0.4 min (95% A, 5% B), gradient to T=0.8 min (65% A, 35% B), gradient to T=1.20 min (45% A, 55% B), T=2.5 min (0% A, 100% B), gradient to T=3.30 min (0% A, 100% B), gradient to T=3.31 min, gradient to end of run at T=4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Runtime: 4 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: -default, Desolvation gas flow rate: -default.

[0279] Method U Waters Acquity UPLC-H Class with PDA and QDa detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: 80℃, autosampler temperature: 15℃, phase A: 5mM ammonium bicarbonate in Milli Q water, mobile phase B: acetonitrile, mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: 1.00 mL / min, runtime: 17 minutes. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: - Default, Desolvation gas flow rate: - Default.

[0280] Method V Agilent 1260 Infinity-II DAD detector (LC / MSD) with Agilent G6125C mass detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 60℃, autosampler temperature: 15℃, mobile phase A: Milli Q 5mM ammonium bicarbonate in water, mobile phase B: acetonitrile, mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: -1.0 mL / min, runtime: -17 min, UV detection method: -DAD. Mass parameters: Probe: MMI, Ionization mode: (ESI) positive and negative, Fragment voltage: -30 and 70V, Capillary voltage: -3000V, Source gas temperature: -325℃, Vaporizer temperature: -225℃, Gas flow rate: -12L / min, Nebulizer: -50

[0281] Method W Waters Acquity UPLC-H Class with PDA and QDa detector, Column: Welch Xtimate C18, 150×4.6mm, 5 microns, Column temperature: Ambient, Autosampler temperature: 15℃, Phase A: Milli Q 5mM ammonium bicarbonate in water, Mobile phase B: Acetonitrile, Mobile phase gradient details: T=0 min (90% A, 10% B), T=7.0 min (10% A, 90% B), Gradient to T=9.0 min (0% A, 100% B), Gradient to T=14.00 min (0% A, 100% B), T=14.01 min (90% A, 10% B), End of run at T=17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: - Default, Desolvation gas flow rate: - Default.

[0282] Method X Waters Acquity UPLC-H Class with PDA and QDa detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: Milli Q 0.05% trifluoroacetic acid in water, mobile phase B: acetonitrile, mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: 1.00 mL / min, runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: - Default, Desolvation gas flow rate: - Default.

[0283] Method Y Waters 996 photodiode array detector with Waters Micromass ZQ detector, column: XTIMATE C18 5μm 4.6×150mm, column temperature: 35℃, autosampler temperature: 15℃, mobile phase A: 0.05% trifluoroacetic acid in Milli Q water (pH=3.50), mobile phase B: acetonitrile. Mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B). Flow rate: -1.0 mL / min, runtime: -17 min, UV detection method: -PDA. Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: -30 and 10V, Capillary voltage: -3.0KV, Extraction voltage: -2V, Rf lens: -0.1V, Source temperature: -120℃, Probe temperature: -400℃, Cone gas flow rate: -100L / hour, Desolvation gas flow rate: -800L / hour.

[0284] Method Z Waters Acquity UPLC-H Class with PDA and SQd detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile, mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: 1.00 mL / min, runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 3.0KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0285] Method A1 Waters Acquity UPLC-H Class with PDA and SQd detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile, mobile phase gradient details: T=0 min (100% A, 0% B), T=7.0 min (50% A, 50% B), gradient to T=9.0 min (0% A, 100% B), gradient to T=14.00 min (0% A, 100% B), T=14.01 min (100% A, 0% B), end of run at T=17 min (100% A, 0% B), flow rate: 1.00 mL / min, runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 3.0KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0286] Method A2 Waters Acquity UPLC with PDA and SQd detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase A: 0.05% trifluoroacetic acid in Milli Q water (pH=3.50), mobile phase B: acetonitrile. Mobile phase gradient details: T=0 min (100% A, 0% B), T=7.0 min (50% A, 50% B), gradient to T=9.0 min (0% A, 100% B), gradient to T=14.00 min (0% A, 100% B), T=14.01 min (100% A, 0% B), end of run at T=17 min (100% A, 0% B), flow rate: 1.00 mL / min, runtime: 17 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 3.0KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0287] Method A3 Waters Acquity UPLC-H Class with PDA and QDa detector, column: Welch Xtimate C18, 150×4.6mm, 5 microns, column temperature: ambient, autosampler temperature: 15℃, mobile phase: 5mM ammonium bicarbonate in water (pH=7.35), mobile phase B: acetonitrile. Mobile phase gradient details: T=0 min (100% A, 0% B), T=7.0 min (50% A, 50% B), gradient to T=9.0 min (0% A, 100% B), gradient to T=14.00 min (0% A, 100% B), T=14.01 min (100% A, 0% B), end of run at T=17 min (100% A, 0% B), flow rate: 1.00 mL / min, runtime: 17 minutes. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 0.8KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: - Default, Desolvation gas flow rate: - Default.

[0288] Method A4 Waters Acquity UPLC-H Class with PDA and SQd detector, column: X-Bridge BEH C18, 50×2.1mm, 2.5 microns, Column temperature: Ambient, Autosampler temperature: 15℃, Mobile phase A: 2mM ammonium acetate followed by 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile, Mobile phase gradient details: T=0 min (95% A, 5% B) flow rate, T=0.4 min (95% A, 5% B), gradient to T=0.8 min (65% A, 35% B), gradient to T=1.20 min (45% A, 55% B), T=2.5 min (0% A, 100% B), gradient to T=3.30 min (0% A, 100% B), gradient to T=3.31 min, gradient to end of run at T=4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Runtime: 4 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 3.0KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0289] Method A5 Waters Acquity UPLC with PDA and SQd detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 microns, column temperature: ambient, autosampler temperature: 150°C, mobile phase A: 5 mM ammonium bicarbonate in water (pH=8.0), mobile phase B: acetonitrile. Mobile phase gradient details: Flow rate at T=0 min (95%A, 5%B), gradient to T=0.4 min (95%A, 5%B), gradient to T=0.8 min (65%A, 35%B), gradient to T=1.20 min (45%A, 55%B), gradient to T=2.5 min (0%A, 100%B), gradient to T=3.30 min (0%A, 100%B), gradient to T=3.31 min, gradient to end of run at T=4 min (95%A, 5%B), flow rate: 0.55 mL / min, runtime: 4 min. UV detection method: PDA Mass parameters: Probe: ESI, Ionization mode: Positive and negative, Cone voltage: 10V and 30V, Capillary voltage: 3.0KV, Extraction voltage: 1KV, Rf lens: 0.1, Source temperature: 120℃, Probe temperature: 600℃, Cone gas flow rate: Default, Desolvation gas flow rate: Default

[0290] LC-Method 1 UPLC-MS was performed using an Acquity UPLC HSS Shield RP18 1.7μm 100×2.1mm (Plus Guard cartridge) column maintained at 40°C with a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer. The column was first maintained for 0.4 minutes in 5% acetonitrile (far-UV grade) with 0.1% (V / V) formic acid / water with 0.1% formic acid (high purity using PureLab Option unit), followed by a linear gradient from 5% to 95% over 6.4 minutes and then maintained at 95% for 1.2 minutes (F=0.4mL / min).

[0291] LC-Method 2 UPLC-MS was performed using an Acquity UPLC BEH Shield RP18 1.7μm 100×2.1mm (Plus Guard cartridge) column maintained at 40°C on a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer. The column was initially maintained in 5% acetonitrile / water (containing 10mM ammonium bicarbonate) for 0.4 minutes, followed by a linear gradient of 5–95% over 6.4 minutes, and then maintained at 95% for 1.2 minutes (F=0.4mL / min).

[0292] LC-Method 3 UPLC-MS was performed using an Acquity UPLC BEH C18 1.7um 100×2.1mm (Plus Guard cartridge) column maintained at 40°C with a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer. The column was first maintained for 0.4 minutes in 5% acetonitrile (far-UV grade) with 0.1% (V / V) formic acid / water with 0.1% formic acid (high purity using PureLab Option unit), followed by a linear gradient from 5% to 95% over 6.4 minutes and then maintained at 95% for 1.2 minutes (F=0.4mL / min).

[0293] LC-Method 4 UPLC-MS was performed using an Acquity UPLC BEH C18 1.7um 100×2.1mm (Plus Guard cartridge) column maintained at 40°C on a Waters DAD+Waters SQD2 single quadrupole UPLC-MS spectrometer. The column was initially maintained in 5% acetonitrile / water (containing 0.1% v / v ammonium hydroxide) for 0.4 minutes, followed by a linear gradient from 5% to 95% over 6.4 minutes and then maintained at 95% for 1.2 minutes (F=0.4 mL / min).

[0294] Analytical HPLC method Method B Instrument details: Agilent 1260 Series with PDA detector, column temperature: 25°C, autosampler temperature: 25°C, mobile phase A: 0.05% trifluoroacetic acid in Milli Q water (pH=2.1), mobile phase B: acetonitrile (100%).

[0295] Mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: -1.0 mL / min, runtime: -17 min, UV detection method: -PDA.

[0296] Method C Instrument details: Water alliance e2695 with -2998 PDA detector, column temperature: 25°C, autosampler temperature: 25°C, mobile phase A: 0.1% ammonium hydroxide solution in HPLC water, mobile phase B: acetonitrile (100%).

[0297] Mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: -1.0 mL / min, runtime: -17 min, UV detection method: -PDA.

[0298] Method D Instrument details: Shimadzu i-series LC-2050C with PDA detector, column temperature: 25°C, autosampler temperature: 25°C, mobile phase A: 0.05% trifluoroacetic acid in Milli Q water (pH=2.1), mobile phase B: acetonitrile (100%).

[0299] Mobile phase gradient details: T=0 min (90%A, 10%B), T=7.0 min (10%A, 90%B), gradient to T=9.0 min (0%A, 100%B), gradient to T=14.00 min (0%A, 100%B), T=14.01 min (90%A, 10%B), end of run at T=17 min (90%A, 10%B), flow rate: -1.0 mL / min, runtime: -17 min, UV detection method: -PDA

[0300] NMR 1 Nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker instrument operating at 400 MHz near room temperature with the solvents described, unless otherwise specified. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million, using conventional abbreviations of the major peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

[0301] Purification method Preparative reverse-phase HPLC conditions Preparative HPLC purification was performed by reverse-phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system such as the Gilson Trilution UV directed system. The Waters 2767 liquid handler functioned as both an autosampler and a fraction collector. Unless otherwise specified, the columns used for preparative purification of compounds were 10 μm 19 × 150 mm Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl, Waters Xbridge Phenyl, or Waters CSH Phenyl Hexyl, 19 × 150, 5 μm columns. Appropriate focus gradients were selected based on acetonitrile and methanol solvent systems under acidic or basic conditions. The modifiers used under acidic / basic conditions were formic acid or TFA (0.1% V / V) and ammonium bicarbonate (10 mM), respectively. Purification was controlled by monitoring at 210–400 nm using Waters Fractionlynx software. Using a 260 nm collection threshold as a trigger, the presence of the target molecular ion was observed under API conditions when using Fractionlynx. The collected fractions were analyzed by LC-MS (Waters Acquity systems with Waters SQD).

[0302] The following is a list of the methods and conditions used for preparative reverse-phase HPLC purification.

[0303] [Table 1]

[0304] [Table 2]

[0305] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol Enantiomer separation of compounds was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with Stacked Injection Module). The Waters 2767 liquid handler functioned as both an autosampler and a fraction collector. Methods without a suitable gradient were selected based on methanol, ethanol, or isopropanol solvent systems under unmodified or basic conditions. The standard SFC method used was modifier, CO2, 100 mL / min, 120 bar back pressure, and 40°C column temperature. The modifier used under basic conditions was diethylamine (0.1% V / V). The modifier used under acidic conditions was formic acid (0.1% V / V) or TFA (0.1% V / V). SFC purification was controlled by Waters Fractionlynx software, monitored from 210 to 400 nm, with a collection threshold, typically 260 nm, as the trigger. The collected fractions were analyzed by SFC (Waters / Thar SFC systems with Waters SQD). The fractions containing the desired product were concentrated by vacuum centrifugation.

[0306] The following is a list of SFC methods and conditions used for enantiomer splitting or enantiomer purity determination.

[0307] [Table 3]

[0308] Preparation of compounds Example 1: (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide Step 1: (3-Chloro-4,6-dihydroxy-2-methylphenyl)(4-(methylamino)isoindorin-2-yl)methanone [ka] To a stirred solution of 3-chloro-4,6-dihydroxy-2-methylbenzoic acid (intermediate B) (0.4 g, 1.97 mmol, 1 equivalent) in DMF (4 mL), EDC.HCl (0.56 g, 2.96 mmol, 1.5 equivalents) and HOAT (0.26 g, 1.97 mmol, 1 equivalent) were added at 0°C. Methylisoindoline-4-amine hydrochloride (intermediate A) (0.43 g, 2.36 mmol, 1.2 equivalents) and methylmorpholine (0.99 g, 9.87 mmol, 5 equivalents) were added, and the mixture was stirred at 0°C for 10 minutes, then at room temperature for 30 minutes. The resulting mixture was poured into ice-cold water (50 mL) and extracted with SiO2 (3 × 30 mL). The combined organic extract was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica chromatography (the product was eluted with 4% MeOH in DCM) to obtain the labeled compound as a grayish-white solid (0.3 g, yield: 22.8%).

[0309] 1 H NMR(DMSO-d6,400MHz):δ 2.13(s,3H),2.61-2.72(dd,J=4Hz,3H),4.10-4.47(m,2H),4.56(s,1H),4.70(s,1H),5.34-5.52(dd,J=4Hz,1H,D2O exchangeable ),6.34-6.40(m,1H),6.44-6.48(m,2H),7.06-7.13(m,1H),9.75(d,J=8Hz,1H,D2O replaceable),10.10(d,J=4Hz,1H,D2O replaceable).

[0310] LCMS (Method A): 1.482 min, 1.592 min, MS: ES+332.8 (M+1).

[0311] Step 2: (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] The procedure was carried out in two parallel batches, each on a 0.15 g scale: (E)-4-(dimethylamino)buta-2-enoic acid (CAS: 848133-35-7) (0.15 g, 0.90 mmol, 1.0 equivalent) was stirred in DMF (1.5 mL) to which (3-chloro-4,6-dihydroxy-2-methylphenyl)(4-(methylamino)isoindorin-2-yl)methanone (Step 1) (0.15 g, 0.45 mmol, 0.5 equivalent) and DCC (0.28 g, 1.35 mmol, 1.5 equivalent) were added. The reaction mixture was heated to 150°C for 15 minutes using microwave irradiation. The resulting mixture was diluted with water (30 mL) and extracted with ELISA (2 × 15 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by preparative HPLC to obtain the labeled compound (0.04 g, yield: 10%).

[0312] high temperature 1 H NMR(DMSO-d6,400MHz,348K):δ 2.10-2.15(s,3H),2.63-2.83(m,6H),3.10(s,3H),3.73-3.77(m,2H),4.26-4.87(m,4H),5.98-6.10(m,1H),6.44 -6.50(m,1H),6.59-6.74(m,1H),7.22-7.26(m,1H),7.34-7.47(m,2H),9.87(d,J=12Hz,1H),10.19-10.21(m,1H).

[0313] LCMS (Method A): 1.085 min, MS: ES+443.9(M+1).

[0314] Analytical HPLC (Method D): 4.78 minutes

[0315] Preparative HPLC purification method Chromatographic separation and isolation were performed using a Shimazu NEXERA purification system equipped with a UV detector; the column was a Shim-Pack GIST C18 (250 mm × 20 mm × 5 μm). The compounds were eluted with mobile phase A: 0.05% TFA in water and mobile phase B: acetonitrile, using gradients of T=0 min (85% A, 15% B), T=21.00 min (62% A, 38% B), T=21.01 min (2% A, 98% B), T=23.0 min (2% A, 98% B), T=23.01 min (85% A, 15% B), and T=26.00 min (85% A, 15% B). Flow rate = 20 mL / min, analysis time 26 minutes.

[0316] Example 1.1: (E)-N-benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide Step 1: (4-(benzylamino)isoindolin-2-yl)(2,4-dihydroxyphenyl)methanone [ka] The compound in question was prepared from N-benzylisoindoline-4-amine hydrochloride (intermediate E) and 2,4-dihydroxybenzoic acid (CAS 89-86-1) by a method similar to that of Step 1 in Example 1.

[0317] 1 H NMR(DMSO-d6,400MHz):δ 2.73(s,1H),2.89(s,1H),4.31(d,J=20Hz,2H),4.70(t,J=12Hz,4H),6.11-6.54(m,5H),6. 96(d,J=8Hz,1H),7.20-7.35(m,5H),9.72(s,1H,D2O replaceable),10.56(d,J=36Hz,1H,D2O replaceable).

[0318] LCMS (Method A): 2.012 min, MS: ES+361(M+1)

[0319] Step 2: (E)-N-benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide [ka] The indicated compound was prepared from (4-(benzylamino)isoindorin-2-yl)(2,4-dihydroxyphenyl)methanone (Step 1) and (E)-4-(dimethylamino)buta-2-enoic acid salt (CAS: 848133-35-7) by a method similar to Step 2 of Example 1.

[0320] 1 H NMR(DMSO-d6,400MHz):δ 1.99(s,6H),2.86(s,br,2H),4.07-4.32(m,1H),4.44-4.57(m,1H),4.79(s,3H),5.01(d,J=12Hz,1H),5.72(t,J=12Hz,1H), 6.27-6.32(m,2H),6.71-6.91(m,3H),6.98(d,J=8Hz,1H),7.11-7.31(m,6H),9.73(s,1H,D2O replaceable),10.34(s,1H,D2O replaceable).

[0321] LCMS (Method A): 1.272 min, MS: ES+472.2 (M+1).

[0322] Analytical HPLC (Method B): 4.737 minutes

[0323] Example 1.2: (E)-N-benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide Step 1: (4-(benzylamino)isoindolin-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone [ka] The compound in question was prepared from N-benzylisoindoline-4-amine hydrochloride (intermediate E) and 2,4-dihydroxy-5-methylbenzoic acid (intermediate F) by a method similar to that of Step 1 in Example 1.

[0324] 1 H NMR(DMSO-d6,400MHz):δ 2.07(s,3H),4.28-4.33(m,2H),4.65-4.72(m,4H),6.08-6.27(m,2H),6.40-6.52(m,2H),6.96(s,1H),7 .07(s,1H),7.19(s,1H),7.30-7.36(m,4H),9.64(d,J=8Hz,1H,D2O exchangeable),10.12-10.22(m,1H,D2O exchangeable).

[0325] LCMS (Method A): 2.124 min, MS: ES+375.1(M+1)

[0326] Step 2: (E)-N-benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide [ka] The indicated compound was prepared from (4-(benzylamino)isoindorin-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone (Step 1) and (E)-4-(dimethylamino)buta-2-enoic acid salt (CAS: 848133-35-7) by a method similar to Step 2 of Example 1.

[0327] 1H NMR(DMSO-d6,400MHz):δ 2.01(s,6H),2.08(s,3H),2.89(s,br,2H),4.06(d,J=16Hz,1H),4.28(d, J=16Hz,1H),4.43-4.56(m,1H),4.78(s,4H),5.01(d,J=16Hz,1H),5.74( d,J=16Hz,1H),6.38(s,1H),6.60-6.79(m,2H),6.90(d,J=8Hz,2H),7.18-7.34(m,7H),9.65(s,1H,D2O replaceable),9.89 and 10.06(singlet,1H,D2O replaceable).

[0328] LCMS (Method A): 1.372 min, MS: ES+486.2 (M+1).

[0329] Analytical HPLC (Method B): 4.93 min.

[0330] Example 1.3: (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(diethylamino)-N-((1-methyl-1H-pyrazole-4-yl)methyl)buta-2-enamide Step 1: (2,4-dihydroxyphenyl)(4-(((1-methyl-1-pyrazole-4-yl)methyl)amino)isoindoline-2-yl)methanone [ka] The compound in question was prepared from N-((1-methyl-1H-pyrazole-4-yl)methyl)isoindoline-4-amine (intermediate L) and 2,4-dihydroxybenzoic acid (CAS 89-86-1) by a method similar to that of Step 1 in Example 1.

[0331] 1H NMR(DMSO-d6,400MHz):δ 3.75(s,3H),4.02-4.13(m,2H),4.61-4.72(m,4H),5.69(s,1H) D2O replaceable), 6.29-6.33(m,2H),6.46-6.57(m,2H),7.04(d,J=6.8Hz,1H),7.24(d,J=8.8Hz,1H),7.34 (d,J=16.8Hz,1H),7.55(d,J=16Hz,1H).9.72(s,1H,D2O replaceable),10.5 and 10.6(2 singlet,1H,D2O replaceable)

[0332] LCMS (Method A): 1.468 min, MS: ES+365(M+1).

[0333] Step 2: (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(diethylamino)-N-((1-methyl-1-pyrazole-4-yl)methyl)buta-2-enamide [ka] The indicated compound was prepared from (2,4-dihydroxyphenyl)(4-(((1-methyl-1H-pyrazole-4-yl)methyl)amino)isoindorin-2-yl)methanone (Step 1) and (E)-4-(dimethylamine)buta-2-enoside salt (CAS: 848133-35-7) by a method similar to Step 2 of Example 1.

[0334] 1 H NMR(DMSO-d6,400MHz,D2O exchange)δ 2.06(s,6H),2.95(s,br,2H),3.69-3.82(m,3H),4.35-4.83(m,6H),5.67-5.77 (m,1H),6.28-6.33(m,2H),6.70(bs,1H),6.98-7.15(m,3H),7.35-7.51(m,3H).

[0335] LCMS (Method A): 0.977 min, MS: ES+475.1 (M+1).

[0336] Analytical HPLC (Method D): 4.392 min.

[0337] Preparative HPLC purification method. Chromatographic separation and isolation were performed on a Shimadzu Nexera prep equipped with an Lh-40 automated purification system. The column used was a Shim-Pack GIST C18 (250 mm × 20 mm × 5 μm). The compounds were eluted using mobile phase A: 0.05% formic acid in water and mobile phase B: methanol, with gradients of T=0.01 min (87% A, 13% B), T=24.00 min (63% A, 37% B), T=24.01 min (2% A, 98% B), T=26.00 min (2% A, 98% B), T=26.01 min (87% A, 13% B), and T=30 min (87% A, 13% B). Flow rate = 14 mL / min, analysis time 30 minutes.

[0338] Example 2: (E)-4-(3,3-difluoropyrrolidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide Step 1: (E)-N-(2-(2,4-bis(methoxymethoxy)-5-methylbenzoyl)isoindorin-4-yl)-4-(3,3-difluoropyrrolidine-1-yl)buta-2-enamide [ka] To a cooled (0°C) solution of (E)-4-(3,3-difluoropyrrolidine-1-yl)buta-2-enoic acid (intermediate D) (0.35 g, 1.83 mmol, 1.0 equivalent) in DCM (3.5 mL), CO2Cl2 (1.7 mL) and a catalytic amount of DMF (2-3 drops) were added under nitrogen, and the mixture was stirred at 0°C for 15 minutes. The resulting mixture was concentrated under reduced pressure (under nitrogen), the intermediate was dissolved in THF (3.5 mL), and cooled to 0°C. To this mixture, a solution of (4-aminoisoindorin-2-yl)(2,4-bis(methoxymethoxy)-5-methylphenyl)methanone (intermediate C) (0.2 g, 0.49 mmol, 0.3 equivalent) and DIPEA (0.7 g, 5.49 mmol, 3.0 equivalent) was added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extract was dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by silica chromatography (the product was eluted with 3.6% MeOH in DCM) to obtain the labeled compound (0.16 g, yield: 31%). 1 H NMR(DMSO-d6,400MHz):δ 2.14(s,3H),2.20-2.34(m,2H),2.67-2.78(m,2H),2.86-2.98(m,2H),3.24-3.25( m,1H),3.28-3.31(m,4H),3.42(s,3H),4.59(s,br,2H),4.80(d,J=14.8Hz,2H),5.1 7(s,2H),5.26(s,2H),6.56-6.80(m,2H),6.92(d,J=3.6Hz,1H),7.04(d,J=7.6Hz, 1H),7.13-7.17(m,2H),7.26-7.30(q,J=7.6Hz,15.6Hz,1H),7.67(t,J=7.6Hz,1H).

[0339] LCMS (Method A): 1.335 min, 1.420 min, 1.487 min, 1.518 min, MS: ES+546 (M+1).

[0340] Step 2: (E)-4-(3,3-difluoropyrrolidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide [ka] (E)-N-(2-(2,4-bis(methoxymethoxy)-5-methylbenzoyl)isoindorin-4-yl)-4-(3,3-difluoropyrrolidine-1-yl)buta-2-enamide (Step 1) (0.16 g, 0.29 mmol, 1.0 equivalent) was stirred in EtOH (1.6 mL), to which 4 M HCl (0.8 mL) in dioxane was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure to obtain the labeled compound (0.045 g, yield: 34%).

[0341] 1 H NMR(DMSO-d6,400MHz):δ 2.03(s,3H),2.27-2.33(m,2H),2.67-2.74(m,2H),2.91-2.94(m,2H),3.27-3.34(m,2H),4.70-4.80(m,4H),6.31(s,1H),6.65-6. 75(m,1H),7.06-7.15(m,2H),7.26-7.27(m,1H),7.66(d,J=7.2Hz,1H),9.63-9.72(m,2H,D2O exchangeable),9.98-10.17(m,1H,D2O exchangeable).

[0342] LCMS (Method A): 1.208 min, MS: ES+458(M+1).

[0343] Analytical HPLC (Method B): 4.638 min.

[0344] Preparative HPLC purification method. Chromatographic separation and isolation were performed using a Waters 2545 purification system equipped with a UV detector. The column used was SUNFIRE, C18, OBD (19×250) mm, 5 μm. The compounds were eluted with mobile phase A: 0.05% formic acid in water and mobile phase B: acetonitrile, using gradients of T=0 min (75% A, 25% B), T=17.00 min (65% A, 35% B), T=17.01 min (0.2% A, 98% B), T=20.00 min (0.2% A, 98% B), T=20.01 min (75% A, 25% B), and T=24 min (75% A, 25% B). Flow rate = 13 mL / min, analysis time 24 minutes.

[0345] Example 2.1: ((E)-4-(3,3-difluoroazetidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide Step 1: (E)-N-(2-(2,4-bis(methoxymethoxy)-5-methylbenzoyl)isoindorin-4-yl)-4-(3,3-difluoroazetidine-1-yl)buta-2-enamide [ka] The indicated compound was prepared from (E)-4-(3,3-difluoroazetidine-1-yl)buta-2-enoic acid (intermediate DA) and (4-aminoisoindorin-2-yl)(2,4-bis(methoxymethoxy)-5-methylphenyl)methanone (intermediate C) by a method similar to that of Step 1 in Example 2. The compound was used directly in Step 2. LCMS (Method A): 1.410 min, 1.437 min, 1.521 min, 1.546 min, MS: ES+535.1 (M+1).

[0346] Step 2: ((E)-4-(3,3-difluoroazetidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide [ka] The compound in question was prepared from (E)-N-(2-(2,4-bis(methoxymethoxy)-5-methylbenzoyl)isoindorin-4-yl)-4-(3,3-difluoroazetidine-1-yl)buta-2-enamide and 4M HCl in dioxane by a method similar to that of Step 2 of Example 2.

[0347] high temperature 1 H NMR(DMSO-d6,400MHz,348K):δ 2.07(s,3H),3.40(d,J=4Hz,2H),3.63-3.69(t,J=12Hz,4H),4.83(d,J=12.8Hz,4H),6.35-6.40(m,2H),6.69-6.74(m,1 H),7.11(d,J=8.8Hz,2H),7.29-7.25(t,J=8Hz,1H),7.64(d,J=8Hz,1H),9.43(m,2H,D2O exchangeable),10.08(s,1H,D2O exchangeable).

[0348] LCMS (Method A): 1.208 min, MS: ES+444(M+1).

[0349] Analytical HPLC (Method B): 4.514 minutes

[0350] Preparative HPLC purification method Chromatographic separation and isolation were performed using a Waters 2545 purification system equipped with a UV detector. The column used was a SUNFIRE, C18, OBD 19×250 mm, 5 μm column. The compounds were eluted using mobile phase A: 0.05% formic acid in water and mobile phase B: 20% acetonitrile, with gradients of T=0 min (78% A, 22% B), T=15.00 min (68% A, 32% B), T=15.01 min (2% A, 98% B), T=18.00 min (2% A, 98% B), T=18.01 min (78% A, 22% B), and T=24.00 min (78% A, 22% B). Flow rate = 19 mL / min, analysis time 24 minutes.

[0351] Example 3: N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide Step 1: (2,4-dihydroxy-5-methylphenyl)(4-nitroisoindolin-2-yl)methanone: [ka] The compound in question was prepared from 2,4-dihydroxy-5-methylbenzoic acid (intermediate F) and 4-nitroisoindoline hydrochloride (intermediate C, step 1c) by a method similar to that of step 1 in Example 1.

[0352] 1 H NMR(DMSO-d6,400MHz):δ 2.04(s,3H),4.90(s,2H),5.19(s,br,2H),6.43(s,1H),7.06(s,br,1H),7.62(t,J=8Hz,1H),7.78 -7.84 (m, 2H), 8.15 (d, J=8.4Hz, 1H), 9.68 (s, 1H, D2O exchangeable), 9.97 and 10.1 (singlet, br, 1H, D2O exchangeable).

[0353] LCMS (Method A): 1.606 min, MS: ES+315.1 (M+1).

[0354] Step 2: (4-aminoisoindolin-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone [ka] (2,4-dihydroxy-5-methylphenyl)(4-nitroisoindorin-2-yl)methanone (Step 1) (1.0 g, 3.18 mmol, 1 equivalent) was stirred in EtOH (10 mL) and water (5 mL). NH4Cl (2.53 g, 4.78 mmol, 15.0 equivalents) and Fe powder (2.14 g, 38.21 mmol, 6.0 equivalents) were added, and the reaction mixture was heated at 70°C for 3 hours. The resulting mixture was filtered through Celite®, and the filter cake was washed with 10% MeOH:DCM (4 × 100 mL). The filtrate was poured into water (200 mL) and extracted with siRNA (3 × 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum to obtain the marked compound as a brown solid (0.8 g, yield: 94%). 1 H NMR (MeOD-d6, 400MHz): δ 2.14(s,3H),4.77(s,br,2H),4.92(s,br,2H),6.39(s,br,1H),6.63(s,br,2H),7.06-7.14(m,2H).

[0355] LCMS (Method A): 1.287 min, MS: ES+284.79 (M+1).

[0356] Step 3: N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide [ka] (4-aminoisoindolin-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone (Step 2) (0.200 g, 0.704 mmol, 1 equivalent) was stirred in acetic acid (2 mL) and acrylic anhydride (0.089 g, 0.704 mmol, 1 equivalent) was added dropwise at 0°C. The resulting mixture was allowed to stand and warmed to room temperature, then stirred for 2 hours. The resulting mixture was poured into ice-cold water (100 mL), neutralized with a saturated solution of K2CO3 (pH approximately 10), and extracted with siRNA (3 × 50 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The crude material was purified by silica chromatography (the product was eluted with 3.4% MeOH in DCM) to obtain the marked compound as a grayish-white solid (0.065 g, yield: 27.3%).

[0357] high temperature 1 H NMR(DMSO-d6,400MHz):δ 2.07(s,3H),4.82-4.86(m,4H),5.73-5.76(m,1H),6.25-6.29(m,1H),6.41(s,1H),6.50-6.57(m,1H),7 .12(d,J=6.8Hz,2H),7.28(t,J=7.6Hz,1H),7.62(d,J=8Hz,1H),9.40(s,1H),9.58(s,1H),10.09(s,1H).

[0358] LCMS (Method A): 1.398 min, MS: ES+338.8 (M+1).

[0359] Analytical HPLC (Method B): 6.13 min.

[0360] Example 4: (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide Step 1: tert-butyl(E)-7-(4-(dimethylamino)buta-2-enamide)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] To a stirred solution of (E)-4-(dimethylamino)buta-2-enoside (CAS:848133-35-7) (1 g, 6.02 mmol, 1 equivalent) in DMF (15 mL), EDC.HCl (1.7 g, 9.03 mmol, 1.5 equivalents) and HOAT (0.82 g, 6.02 mmol, 1 equivalent) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (intermediate H) (1.5 g, 6.02 mmol, 1 equivalent) and NMM (1.21 g, 12.04 mmol, 2 equivalents) were added, and stirring was continued at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL) and extracted with SiO2 (4 × 30 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The crude material was purified by silica chromatography (the product was eluted with 3.5% MeOH in DCM) to obtain the labeled compound as a brown solid (3.5 g, yield: quantitative). 1 H NMR(DMSO-d6,400MHz):δ 1.42(s,9H),2.26(s,6H),2.71(t,J=5.6Hz,2H),2.17(t,J=6.0Hz,2H),3.53(t,J=5.6Hz,2H),4.45(s,br,2H),6 .28(d,J=15.2Hz,1H),6.68-6.75(m,1H),7.09(d,J=8.4Hz,1H),7.34-7.38(m,1H),7.50(bs,1H),10.05(s,1H).

[0361] LCMS (Method A): 1.373 min, MS: ES+359.9 (M+1).

[0362] Step 2: (E)-7-(4-(dimethylamino)buta-2-enamide)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] To a cooled (0°C) solution of tert-butyl 7-(4-(dimethylamino)buta-2-enamide)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step 1) (3.5 g, 9.74 mmol, 1 equivalent) in DCM (35 mL), 4 M HCl (35 mL) was added dropwise, and the reaction mixture was stirred at 0°C for 2 hours. The resulting mixture was concentrated under vacuum, the crude material was triturated with diethyl ether (7 × 20 mL), and dried under vacuum to obtain the marked compound as a pale yellow solid (3.0 g, yield: quantitative). 1 H NMR(DMSO-d6,400MHz):δ 2.74(d,J=4.8Hz,6H),2.95(t,J=5.6Hz,2H),3.32(bs,2H),3.91(t,J=5.6Hz,2H),4.22(bs,2H),6.54(d,J=15.6Hz,1H),6 .77-6.85(m,1H),7.17(d,J=8.4Hz,1H),7.50-7.55(m,1H),7.61(s,1H),9.57(bs,2H),10.66(s,1H),11.12(bs,1H).HCl salt.

[0363] LCMS (Method C): 4.186 min, MS: ES+260.2 (M+1).

[0364] Step 3: (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide [ka] To a stirred solution of 2,4-dihydroxy-6-methylbenzoic acid (intermediate G) (0.3 g, 1.78 mmol, 1 equivalent) in DMF (15 mL), EDC.HCl (0.513 g, 2.67 mmol, 1.5 equivalents) and HOAT (0.242 g, 1.78 mmol, 1 equivalent) were added at room temperature, and the mixture was stirred for 30 minutes. (E)-4-(dimethylamino)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)buta-2-enamide hydrochloride (step 2) (0.632 g, 2.14 mmol, 1.2 equivalents) and NMM (0.97 mL, 8.90 mmol, 5 equivalents) were added, and stirring was continued at room temperature for 16 hours. The resulting mixture was directly purified by reverse-phase purification (the product was eluted in 50% acetonitrile water). The substance was further tritulated with MeOH (3 × 5 mL) to obtain the labeled compound as a gray solid (0.143 g, yield: 20%).

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

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

[0367] Analytical HPLC (Method B): 4.357 min.

[0368] Example 4.1: (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide [ka] To a stirred solution of 2,4-dihydroxy-5-methylbenzoic acid (intermediate F) (0.2 g, 1.19 mmol, 1 equivalent) in DMF (5 mL), EDC.HCl (0.342 g, 1.78 mmol, 1.5 equivalents) and HOAT (0.161 g, 1.18 mmol, 1 equivalent) were added, and the mixture was stirred at room temperature for 10 minutes. (E)-4-(dimethylamino)-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)buta-2-enamide (Example 4 Step 2) (0.422 g, 1.42 mmol, 1.2 equivalents) and NMM (0.600 g, 5.94 mmol, 5 equivalents) were added, and stirring was continued at room temperature for 1.5 hours. The resulting mixture was poured into water (10 mL) and extracted with SiO2 (3 × 10 mL). The combined organic extracts were washed with cold brine (2 × 10 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by preparative HPLC, and the product fraction was subsequently freeze-dried to obtain the labeled compound (0.160 g, yield: 15.00%).

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

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

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

[0372] Preparative HPLC purification method: Chromatographic separation and isolation were performed using flash chromatography-Selekt with a UV detector; column: YMC C18, 120 gm, 50 μm. The compounds were eluted with mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, using gradients of T=0 min (100% A, 00% B), T=25.00 min (80% A, 20% B), T=25.01 min (00% A, 100% B), T=30.00 min (00% A, 100% B), T=30.01 min (100% A, 00% B), and T=35 min (100% A, 00% B). Flow rate = 70 mL / min, analysis time 35.01 min.

[0373] Example 4.2: (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)methylbuta-2-enamide Step 1: tert-butyl(E)-7-(4-(dimethylamino)methylbuta-2-enamide)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] The experiment was carried out in six parallel batches, each on a 0.5g scale: (E)-4-(dimethylamino)buta-2-enoside (CAS:848133-35-7) (0.5g, 3.01 mmol, 1.0 equivalent) was stirred in DMF (0.5mL), to which tert-butyl 7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (intermediate I) (0.395g, 1.50 mmol, 0.5 equivalent) and DCC (0.927g, 4.5 mmol, 1.5 equivalent) were added. The reaction mixture was heated to 150°C for 15 minutes using microwave irradiation. The resulting mixture was diluted with ice water (200mL) and extracted with ELISA (5×50mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by silica chromatography (the product was eluted with 4.1% MeOH in DCM) to obtain the labeled compound (2.4 g, yield: 35%), which was used directly in step 2. LCMS (Method A): 1.375 min, MS ES+: 374.2 (M+1).

[0374] Step 2: (E)-4-(dimethylamino)methyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)buta-2-enamide hydrochloride [ka] The compound in question was prepared from tert-butyl(E)-7-(4-(dimethylamino)-N-methylbuta-2-enamide)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step 1) and 4M HCl in dioxane by a method similar to Step 2 of Example 4, and was used directly in Step 3.

[0375] LCMS (Method B): 1.55 min, MS: ES+273.38 (M+1).

[0376] Step 3: (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] The compound in question was prepared from 2,4-dihydroxy-5-methylbenzoic acid (intermediate F) and (E)-4-(dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)buta-2-enamide hydrochloride (step 2) by a method similar to that of Step 3 in Example 4. 1 H NMR(DMSO-d6,400MHz):δ 2.01(s,3H),2.05(s,6H),2.84-2.91(m,4H),3.20(s,3H),3.60-3.63(m,2H),4.60-4.62(m,2H),5.88(d,J=14 .8Hz,1H),6.38(s,1H),6.57-6.64(m,1H),6.85(s,1H),7.05-7.10(m,2H),7.22(d,J=8Hz,1H),9.60(bs,2H).

[0377] LCMS (Method A): 1.123 min, MS: ES+424.11 (M+1).

[0378] Analytical HPLC (Method B): 4.279 min.

[0379] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Waters 2545 purification system equipped with a UV detector. The column used was a SUNFIRE, C18, OBD 19×250 mm, 5 μm column. The compounds were eluted using mobile phase A: 0.05% formic acid in water and mobile phase B: acetonitrile, with gradients of T=0 min (90% A, 10% B), T=17.00 min (82% A, 18% B), T=17.01 min (0.2% A, 98% B), T=19.00 min (0.2% A, 98% B), T=19.01 min (90% A, 10% B), and T=24 min (90% A, 10% B). Flow rate = 15 mL / min, analysis time 24.00 min.

[0380] Example 4.3: (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] The compound in question was prepared from 2,4-dihydroxy-6-methylbenzoic acid (intermediate G) and (E)-4-(dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)buta-2-enamide hydrochloride (Step 2 of Example 4.2) by a method similar to Step 3 of Example 4.

[0381] high temperature 1 H NMR(DMSO-d6,400MHz 348K):δ 2.00(s,3H),2.07(s,6H),2.86-2.90(m,4H),3.22(s,2H),3.53(bs,2H),4.61(bs,2H),5.91(d,J=15.4Hz, 1H),6.15(d,J=22.4Hz,2H),6.57-6.64(m,1H),7.04(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,1H),9.04(bs,2H).

[0382] LCMS (Method A): 1.025 min, MS: ES+424.1(M+1).

[0383] Analytical HPLC (Method B): 4.062 min

[0384] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Waters 2545 purification system equipped with a UV detector. The column used was SUNFIRE, C18, OBD (19×250) mm, 5 μm. The compounds were eluted using mobile phase A: 0.05% formic acid in water and mobile phase B: acetonitrile, with gradients of T=3 min (93% A, 7% B), T=16.00 min (93% A, 7% B), T=16.01 min (2% A, 98% B), T=19.00 min (2% A, 98% B), T=19.01 min (93% A, 7% B), and T=25 min (93% A, 7% B). Flow rate = 19 mL / min, analysis time 25 minutes.

[0385] Example 4.4: (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] The compound in question was prepared from 2,4-dihydroxy-5-isopropylbenzoic acid (intermediate FA) and (E)-4-(dimethylamino)-N-methyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)buta-2-enamide hydrochloride (Step 2 of Example 4.2) by a method similar to Step 3 of Example 4. 1 H NMR(DMSO-d6,400MHz):δ 1.10(d,J=6.8Hz,6H),2.06(s,6H),2.85-2.91(m,4H),3.05-3.08(m,1H),3.20(s,3H),3.37-3.63(m,2H),4.64(s,br,2H),5.85( d,J=13.6Hz,1H),6.39(s,1H),6.57-6.93(m,1H),6.88(s,1H),7.06(d,J=8Hz,1H),7.12(s,1H),7.23(d,J=8Hz,1H),9.58(s,2H).

[0386] LCMS (Method A): 1.337 min, MS: ES+452.1 (M+1).

[0387] Analytical HPLC (Method D): 5.007 min.

[0388] Example 5: (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(pyrrolidine-1-yl)buta-2-enamide [ka] The compound in question was prepared from (E)-4-(pyrroridine-1-yl)buta-2-enoside salt (CAS: 848133-09-5) and (4-aminoisoindoline-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone (Example 3, Step 2) by a method similar to that of Example 1, Step 2. 1 H NMR(DMSO-d6,400MHz):δ 1.71(s,4H),2.00(s,3H),2.50-2.67(m,4H),3.23(d,J=5.2Hz,2H),4.81-4.85(m,4H),6.20-6.22(s,br,1H),6.39(d,J =12Hz,1H),6.75-6.81(m,1H),7.07-7.11(m,2H),7.26(t,J=8Hz,1H),7.68(d,J=8Hz,1H),9.65(s,1H),10.33(bs,2H).

[0389] LCMS (Method I): 1.488 min, MS: ES+422.2 (M+1).

[0390] Analytical HPLC (Method C): 5.02 min.

[0391] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Shimadzu Nexera purification system equipped with a UV detector. The column used was SHIMPACK GIST C18, (250 × 20) mm, 5 μm. The compounds were eluted with mobile phase A: 0.1% formic acid in water and mobile phase B: acetonitrile, with gradients T=0 min (80% A, 20% B), T=18 min (78% A, 22% B), T=18.01 min (0.2% A, 98% B), T=20.00 min (0.2% A, 98% B), and from T=20.01 min (80% A, 20% B) to T=22 min (80% A, 20% B). Flow rate = 20 mL / min, analysis time 22 minutes.

[0392] Example 5.1: (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-morpholinbuta-2-enamide [ka] The compound in question was prepared from (E)-4-morpholinobuta-2-enoside (CAS: 1419865-05-6) and (4-aminoisoindoline-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone (Step 2 of Example 3) by a method similar to Step 2 of Example 1.

[0393] high temperature 1 H NMR(DMSO-d6,400MHz):δ 2.07(s,3H),2.40-2.43(m,4H),3.61-3.63(m,4H),3.62(m,4H),4.82-4.85(m,4H),6.36-6.40(m,2H),6.74-6.78( m,1H),7.10-7.12(m,2H),7.27(t,J=7.6Hz,1H),7.62(d,J=4.6Hz,1H),9.42(bs,1H),9.49(bs,1H),10.09(bs,1H).

[0394] LCMS (Method A): 1.103 min, MS: ES+438.0 (M+1).

[0395] Analytical HPLC (Method B): 4.38 min.

[0396] Example 6: N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)methylacrylamide Step 1: (3-Chloro-4,6-dihydroxy-2-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone [ka] To a stirred solution of 3-chloro-4,6-dihydroxy-2-methylbenzoic acid (intermediate B) (0.7 g, 3.45 mmol, 1 equivalent) in DMF (7 mL), EDC.HCl (0.995 g, 5.18 mmol, 1.5 equivalents) and HOAT (0.469 g, 3.45 mmol, 1 equivalent) were added at 0°C. The mixture was allowed to stand and warmed to room temperature, then treated with N-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine hydrochloride (intermediate J) (0.8 g, 4.14 mmol, 1.2 equivalents) and NMM (1.74 g, 17.27 mmol, 5 equivalents). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was poured into ice-cold water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by silica chromatography (the product was eluted with 4% MeOH:DCM) to obtain the labeled compound as a grayish-white solid (0.18 g, yield: 15%).

[0397] 1 H NMR(DMSO-d6,400MHz):δ 2.00-2.08 (2 singlets, 3H), 2.57-2.69 (m, 5H), 3.35 (s, 1H), 3.59-3.96 (m, 1H), 4.17-4.29 (m, 1H), 4.60-4.70 (m, 1H), 5.49 (s,br,1H,D2O exchangeable),6.11-6.45(m,3H),6.82-6.88(m,1H),9.65(d,J=12Hz,1H,D2O exchangeable),10.08(d,J=2Hz,1H,D2O exchangeable).

[0398] LCMS (Method A): 1.061 min, MS: ES+346.9(M+1)

[0399] Analytical HPLC (Method D): 3.727 minutes

[0400] Step 2: N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide [ka] Each procedure was carried out in two parallel batches on a 0.12 g scale. A cooled (0°C) stirred solution of (3-chloro-4,6-dihydroxy-2-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Step 1) (0.12 g, 0.34 mmol, 1.0 equivalent) in DCM (1.2 mL) was mixed with pyridine (0.26 g, 0.346 mmol, 10.0 equivalents) and acrylic anhydride (0.065 g, 0.52 mmol, 1.5 equivalents), and the mixture was stirred at 0°C for 2 hours. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were dried over Na₂SO₄ and reduced under vacuum. The crude material was purified by silica chromatography (the product was eluted with 3.7% MeOH in DCM) to obtain the labeled compound as a white solid (0.023 g, yield: 8.3%).

[0401] 1 1H NMR (DMSO-d6, 400MHz):δ 1.99 and 2.10 (2 singlets, 3H), 2.71-2.74 (m, 1H), 2.80-2.86 (m, 1H), 3.17-3.24 (2 singlets) Let,3H),3.38-3.43(m,1H),3.68-4.02(m,1H),4.31-4.42(m,1H),4.72-4.85(m,1 H),5.59(t,J=12.8Hz,1H),6.04-6.18(m,2H),6.45(d,J=8Hz,1H),7.04-7.09(m,1 H),7.18-7.26(m,2H),9.65-9.71(m,1H,D2O replaceable),10.11(d,J=4Hz,1H,D2O replaceable).

[0402] LCMS (Method A): 1.459 min, MS ES+: 401 (M+1).

[0403] Analytical HPLC (Method D): 5.471 minutes

[0404] Example 6.1: N-(2-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide Step 1: (5-Chloro-2,4-dihydroxyphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone [ka] The compound in question was prepared from 5-chloro-2,4-dihydroxybenzoic acid (intermediate Q) and N-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine hydrochloride (intermediate J) by a method similar to that of Step 1 in Example 6. This substance was then directly carried out to Step 2.

[0405] LCMS (Method A): 1.016 mins, MS: ES+ 332.9 and 334.6 (M+1 and M+3).

[0406] Step 2: N-(2-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide [ka] The compound in question was prepared from (5-chloro-2,4-dihydroxyphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Step 1), acetic acid, and acrylic anhydride by a method similar to Step 3 of Example 3.

[0407] 1 H NMR (DMSO-d6, 400MHz, D2O exchange): δ 2.83(t,J=5.2Hz,2H),3.21(s,3H),3.58(bs,2H),4.65(bs,2H),5.56(d,J=11.6Hz,1H), 6.09-6.16(m,2H),6.57(s,1H),7.06-7.09(m,2H),7.15(bs,1H),7.24(d,J=8.0Hz,1H).

[0408] LCMS (Method A): 1.423 mins, MS: ES+387 and 389 (M+1 and M+3).

[0409] Analytical HPLC (Method D): 5.538 min.

[0410] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Shimadzu Nexera preparative system with an LH-40 automated purification system. The column used was a Shim-Pack GIST C18 (250 mm × 20 mm × 5 μm). The compounds were eluted using mobile phase A: 0.05% formic acid in water and mobile phase B: acetonitrile, with gradients of T=0.01 min (90% A, 10% B), T=17.00 min (47% A, 53% B), T=17.01 min (2% A, 98% B), T=19.00 min (2% A, 98% B), T=19.01 min (90% A, 10% B), and T=22 min (90% A, 10% B). Flow rate = 22 mL / min, analysis time 22 minutes.

[0411] Example 7.1: (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide Step 1: (5-(tert-butyl)-2-hydroxy-4-methoxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone [ka] To a stirred solution of 5-(tert-butyl)-2-hydroxy-4-methoxybenzoic acid (intermediate N) (0.73 g, 3.25 mmol, 1.0 equivalent) in DMF (15 mL), EDC.HCl (0.93 g, 4.88 mmol, 1.5 equivalents) and HOAT (0.44 g, 3.25 mmol, 1.0 equivalent) were added, and the reaction mixture was stirred at room temperature for 30 minutes. N-methylisoindoline-4-amine hydrochloride (intermediate A) (0.57 g, 3.90 mmol, 1.2 equivalents) and NMM (1.64 g, 16.2 mmol, 5.0 equivalents) were added, and stirring was continued for 3 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under vacuum. The crude material was purified by silica chromatography (the product was eluted with 3.4% MeOH:DCM) to obtain the marked compound as a light brown solid (0.6 g, yield: 18.1%). 1 H NMR(DMSO-d6,400MHz):δ 1.30(s,9H),2.64-2.72(m,3H),3.80(s,3H),4.52-4.72(m,4H),6.37(d,J=6.8Hz ,1H),6.52(t,J=17.6Hz,11.2Hz,2H),7.10(d,J=7.6Hz,2H),10.07-10.28(m,1H).

[0412] LCMS (Method A): 2.463 min. MS:ES+355.1(M+1).

[0413] Analytical HPLC (Method B): 9.85 minutes.

[0414] Step 2: (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] To a solution of 4-(dimethylamino)buta-2-enoside (CAS: 848133-35-7) (0.08 g, 0.48 mmol, 1.0 equivalent) in DMF (1.6 mL, 20 V), DCC (0.198 g, 0.96 mmol, 2.0 equivalents) and (5-(tert-butyl)-2-hydroxy-4-methoxyphenyl)(4-(methylamino)isoindorin-2-yl)methanone (Step 1) (0.07 g, 0.19 mmol, 0.4 equivalents) were added. The reaction mixture was heated to 150 °C for 15 minutes using microwave irradiation. The resulting mixture was diluted with cold water (50 mL) and extracted with SiO2 (3 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by preparative HPLC (0.05% formic acid in water: ACN) to obtain the marked compound as a light brown solid (0.005 g, yield: 2%). 1 H NMR(DMSO-d6,400MHz):δ 1.29(s,9H),2.01(s,6H),2.87(d,J=4.8Hz,2H),3.1-3.20(m,3H),3.80(s,3H),4.59(d,J=15.2Hz,1H),4.71-4.89(m ,3H),5.75(d,J=14Hz,1H),6.49-6.66(m,2H),7.07(s,1H),7.22(d,J=6.8Hz,1H),7.36-7.44(m,2H),10.32(bs,1H).

[0415] LCMS (Method A): 1.529 min. MS:ES+466.1(M+1).

[0416] Analytical HPLC (Method D): 5.84 min.

[0417] Preparative HPLC purification method Chromatographic separation and isolation were performed using an FC-01 flash purification system (Buchi model C810); column: YMC-120GM C18, 50 μm. The compounds were eluted with mobile phase A: 0.1% formic acid in water and mobile phase B: acetonitrile, using gradients of T=initial (100% A, 0% B), T=5.00 min (100% A, 0% B), T=30.00 min (70% A, 30% B), T=30.01 min (0% A, 100% B), T=35.00 min (0% A, 100% B), T=35.01 min (100% A, 0% B), and T=40.00 min (100% A, 0% B). Flow rate = 70 mL / min, analysis time 40 minutes.

[0418] Example 7.2: (E)-N-(2-(5-(tert-butyl)-4-fluoro-2-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide Step 1: (5-(tert-butyl)-4-fluoro-2-hydroxyphenyl)(4-(methylamino)isoindolin-2-yl)methanone [ka] The compound in question was prepared from 5-(butyl)-4-fluoro-2-hydroxybenzoic acid (intermediate OA) and -methylisoindoline-4-amine hydrochloride (intermediate A) by a method similar to that of Step 1 in Example 7.1.

[0419] 1 H NMR(DMSO-d6,400MHz):δ 1.23-1.40 (m, 9H), 2.63 and 2.72 (singlet, 3H), 4.42-4.72 (m, 4H), 5.37-5.52 (m, 1H, D2O exchangeable), 6.37 (d, J=10Hz, 1 H),6.46-6.58(m,1H),6.63-6.68(dd,J=4.4Hz,4.8Hz,1H),7.06-7.15(m,2H),10.29(d,J=17.6,1H,D2O exchangeable).

[0420] LCMS (Method A): 2.242 min, MS: ES+343.1 (M+1).

[0421] Analytical HPLC (Method D): 8.260 minutes

[0422] Step 2: (E)-N-(2-(5-(tert-butyl)-4-fluoro-2-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] The indicated compound was prepared from (E)-4-(dimethylamino)buta-2-enoic acid (CAS: 848133-35-7) and (5-(tert-butyl)-4-fluoro-2-hydroxyphenyl)(4-(methylamino)isoindorin-2-yl)methanone (Step 1) by a method similar to that of Step 2 in Example 7.1.

[0423] 1 H NMR(DMSO-d6,400MHz):δ 1.29(d,J=4.8Hz,9H),2.04(s,6H),2.91(d,J=4.4,2H),3.20 and 3.24(singlet,3H),4.48-4.88(m,4H),5.75(t,J=14. 8Hz,1H),6.57-6.69(m,2H),7.12(d,J=9.6Hz,1H),7.22(d,J=7.6Hz,1H),7.34-7.44(m,2H),10.42(s,1H,D2O exchangeable).

[0424] LCMS (Method A): 1.476 min, MS: ES+454.3 (M+1).

[0425] Analytical HPLC (Method D): 4.760 min.

[0426] Example 8: (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide Step 1: (4,6-dihydroxy-2,3-dimethylphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone [ka] To a stirred solution of 4,6-dihydroxy-2,3-dimethylbenzoic acid (intermediate K) (0.180 g, 0.989 mmol, 1.0 equivalent) in DMF (0.9 mL), EDC.HCl (0.284 g, 1.483 mmol, 1.5 equivalents) and HOAT (0.134 g, 0.989 mmol, 1.0 equivalent) were added, and the mixture was stirred at room temperature for 30 minutes. N-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine hydrochloride (intermediate J) (0.195 g, 0.989 mmol, 1.0 equivalent) was added to DMF (0.9 mL), followed by NMM (0.49 g, 4.94 mmol, 5.0 equivalents), and the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with ice-cold water (100 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried with Na2SO4 and concentrated under vacuum. The crude material was purified by silica chromatography (the product was eluted with 70% siRNA in hexane) to obtain the labeled compound (0.120 g, yield: 37%), which was used directly in step 2.

[0427] LCMS (Method A): 0.998 min, MS: ES+327(M+1).

[0428] Step 2: (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] (E)-4-(dimethylamino)buta-2-enoic acid (CAS: 848133-35-7) (0.122 g, 0.734 mmol, 1.0 equivalent) and (4,6-dihydroxy-2,3-dimethylphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Step 1) (0.120, 0.367 mmol, 0.5 equivalent) were stirred in DMF (1.2 mL), to which DCC (0.227 g, 1.102 mmol, 1.5 equivalent) was added, and the reaction mixture was heated to 150°C for 15 minutes using microwave irradiation. The resulting mixture was diluted with water (100 mL), acidified with dilute HCl, and further extracted with siRNA (3 × 30 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The crude substance was eluted with 0.05% formic acid / ACN in water and purified by preparative HPLC to obtain the labeled compound as a brown solid (0.005 g, yield: 4.00%).

[0429] high temperature 1 H NMR(DMSO-d6,400MHz,348.7K):δ 1.97(s,6H),2.05(s,3H),2.07(s,3H),2.85-2.90(m,4H),4.07(bs,1H),4.39(bs,1H),4.72(bs,2H),5.91(d,J =15.6Hz,1H),6.29(s,1H),6.59-6.62(m,1H),7.02-7.23(m,3H),8.20(s,1H,D2O exchangeable),8.90(s,br,D2O exchangeable).

[0430] LCMS (Method D): 1.431 min, MS: ES+438.4 (M+1).

[0431] Analytical HPLC (Method D): 3.839 min.

[0432] Preparative HPLC purification method Chromatographic separation and isolation were performed using a Shimadzu LC20AP with a UV detector. The column used was a Shim-Pack GIST C18 (250 mm × 20 mm × 5 μm). The compounds were eluted using mobile phase A: 0.05% formic acid in water and mobile phase B: acetonitrile, with gradients of T=0.01 min (88% A, 12% B), T=18.00 min (75% A, 25% B), T=18.01 min (2% A, 98% B), T=20.00 min (2% A, 98% B), T=20.01 min (88% A, 12% B), and T=23 min (88% A, 12% B). Flow rate = 22 mL / min, analysis time 23 minutes.

[0433] Example 9: N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide Step 1: (2,4-dihydroxy-5-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone [ka] To a stirred solution of 2,4-dihydroxy-5-methylbenzoic acid (intermediate F) (0.5 g, 2.97 mmol, 1 equivalent) in DCM:THF (10 mL), EDC.HCl (0.86 g, 4.46 mmol, 1.5 equivalents) and HOAT (0.4 g, 2.97 mmol, 1 equivalent) were added at room temperature. N-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine hydrochloride (intermediate J) (0.58 g, 3.57 mmol, 1.2 equivalents) and NMM (1.5 g, 14.88 mmol, 2 equivalents) were added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (the product was eluted with 4% water:ACN) to obtain the labeled compound as a grayish-white solid (0.4 g, yield: 41.5%).

[0434] LCMS (Method A): 1.025 min, MS: ES+312.9 (M+1). This substance was used directly in step 2.

[0435] Step 2: N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide [ka] To a cooled (0°C) solution of (2,4-dihydroxy-5-methylphenyl)(7-(methylamino)-3,4-dihydroisoquinoline-2(1H)-yl)methanone (0.27 g, 0.86 mmol, 1 equivalent) (Step 1) in pyridine (2.7 mL), acrylic anhydride (0.12 mL, 0.951 mmol, 1.1 equivalents) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was neutralized with saturated citric acid solution (80 mL) and extracted with DCM (3 × 50 mL). The combined organic extract was dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified using preparative HPLC (0.05% formic acid in water: ACN, MeOH, IPA) to obtain the marked compound as a grayish-white solid (0.035 g, yield: 11.6%).

[0436] 1 H NMR(DMSO-d6,400MHz):δ 2.00(s,3H),2.83(t,J=5.2Hz,2H),3.21(s,3H),3.62(s,br,2H),4.64(s,2H),5.56(d,J=11.6.Hz,1H),6.06-6.16(m,2H), 6.39(s,1H),6.85(s,1H),7.07(t,J=8.8Hz,7.65Hz,1H),7.14(s,1H),7.23(d,J=8Hz,1H),9.55(d,J=7.2Hz,2H,D2O exchangeable).

[0437] LCMS (Method A): 1.461 min, MS: ES+367(M+1).

[0438] Analytical HPLC (Method D): 6.203 minutes.

[0439] Example 10: N-benzyl(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)acrylamide [ka] The compound in question was prepared from (4-(benzylamino)isoindorin-2-yl)(2,4-dihydroxyphenyl)methanone (Example 1.1 Step 1), acetic acid, and acrylic anhydride by a method similar to that of Example 3, Step 3. 1 H NMR(DMSO-d6,400MHz):δ 4.32-4.51(m,2H),4.85(s,3H),4.92-4.94(m,1H),5.61(d,J=10.4Hz,1H),6.20-6.34(m,3H) ,6.98(t,J=4.0Hz,1H),7.15-7.24(m,6H),7.34(d,J=4.8Hz,2H),9.55(s,1H),10.32(s,1H).

[0440] LCMS (Method A): 1.729 min, MS: ES+415.1 (M+1).

[0441] Analytical HPLC (Method D): 7.278 min.

[0442] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Waters 2545 purification system equipped with a UV detector. The column used was an Xtimate C18 (250 mm × 21.2 mm × 5 μm), and the compounds were eluted with mobile phase A: 0.05% formic acid in water and mobile phase B: acetonitrile:MeOH:IPA (65:25:10) using gradients of T=initial (55%A, 45%B), T=17.00 min (55%A, 45%B), T=17.01 min (2%A, 98%B), T=19.00 min (2%A, 98%B), T=19.01 min (55%A, 45%B), T=23 min (55%A, 45%B), and T=23 min (55%A, 45%B). Flow rate = 22 mL / min, analysis time 23 minutes.

[0443] Example 10.1: N-benzyl(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide [ka] The compound in question was prepared from (4-(benzylamino)isoindorin-2-yl)(2,4-dihydroxy-5-methylphenyl)methanone (Example 1.2 Step 1), acetic acid, and acrylic anhydride by a method similar to that of Example 3, Step 3.

[0444] 1 H NMR(DMSO-d6,400MHz):δ 2.07(s,3H),4.29-4.54(m,2H),4.84(bs,4H),5.61(d,J=9.2Hz,1H),5.95-6.01(m,1H),6.25(dd,J=2.0,8.4Hz,1H), 6.39(s,1H),6.97-6.99(m,2H),7.17-7.25(m,5H),7.30-7.34(m,2H),9.45(bs,1H,D2O exchangeable),9.97(bs,1H,D2O exchangeable).

[0445] LCMS (Method A): 1.829 min, MS: ES+429.0 (M+1).

[0446] HPLC (Method D): 7.57 minutes.

[0447] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Waters 2545 purification system equipped with a UV detector. The column used was an Xtimate C18 (250 mm × 21.2 mm × 5 μm). The compounds were eluted using mobile phase A: 0.05% formic acid in water, and mobile phase B: 20% line + 10% THF in acetonitrile, with gradients of T=initial (52% A, 48% B), T=24.00 min (52% A, 48% B), T=24.01 min (2% A, 98% B), T=26.01 min (2% A, 98% B), T=26.01 min (52% A, 48% B), T=28 min (52% A, 48% B), and T=28.01 min (52% A, 48% B). Flow rate = 20 mL / min, analysis time 28.01 min.

[0448] Example 11: (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-phenethylbuta-2-enamide Step 1: (2,4-dihydroxyphenyl)(4-(phenethylamino)isoindorin-2-yl)methanone [ka] To a cooled (0°C) solution of 2,4-dihydroxybenzoic acid (CAS 89-86-1) (0.38 g, 1.62 mmol, 1 equivalent) in DMF (4.0 mL), HATU (0.92 g, 2.43 mmol, 1.5 equivalents) and DIPEA (0.45 mL, 3.24 mmol, 2.0 equivalents) were added, and the mixture was stirred at 0°C for 10 minutes. N-phenethylisoindoline-4-amine hydrochloride (intermediate M) (0.25 g, 1.62 mmol, 1 equivalent) was added, and the reaction mixture was allowed to stand, warmed to room temperature, and stirred for 1 hour. The resulting mixture was diluted with ice-cold water (50 mL) and extracted with SiO2 (3 × 50 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The crude material was purified by silica chromatography (the product was eluted with 2.0% MeOH in DCM) to obtain the labeled compound (0.3 g, yield: 47.6%).

[0449] 1¹H NMR (DMSO-d6, 400MHz): δ 2.81-2.89 (m, 2H), 4.59 (d, J=10Hz, 2H), 4.72 (s, 2H), 5.48 (d, J=24.8Hz, 1H), 6.29-6.34 (m, 2H), 6.50-5.59 (m, 2H), 7.09 (d, J=6.8Hz, 1H), 7.21-7.29 (m, 6H), 9.71 (s, 1H, D2O interchangeable), 10.53 (s, 1H, D2O interchangeable). Two protons are hidden beneath the water peak.

[0450] LCMS (Method A): 2.116 min, MS: ES+375.1 (M+1).

[0451] Step 2: (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-phenethylbuta-2-enamide [ka] The compound in question was prepared from (E)-4-(dimethylamine)buta-2-enoside (CAS: 848133-35-7) and (2,4-dihydroxyphenyl)(4-(phenethylamine)isoindorin-2-yl)methanone (Step 1) by a method similar to Step 2 of Example 1.

[0452] 1 H NMR(DMSO-d6,400MHz):δ 2.0(s,6H),2.67-2.87(m,4H),3.70-3.71(m,1H),3.93-4.02(m,1H),4.71-4.88(m,2H),4.53-4.67(m,2H),5.66-5.74(m,1H) ),6.28-6.34(m,2H),6.65-6.73(m,1H),7.08-7.36(m,7H),7.38-7.43(m,2H),9.73(s,1H,D2O exchangeable),10.37(s,1H,D2O exchangeable).

[0453] LCMS (Method A): 1.409 min, MS: ES+486.1 (M+1).

[0454] Analytical HPLC (Method D): 5.03 min.

[0455] Example 11.1: (E)-N-(2-(2-chloro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide Step 1: (2-Chloro-4,6-bis(methoxymethoxy)phenyl)(4-(methylamino)isoindorin-2-yl)methanone [ka] The compound in question was prepared from 2-chloro-4,6-bis(methoxymethoxy)benzoic acid (intermediate P) and N-methylisoindoline-4-amine hydrochloride (intermediate A) by a method similar to that of Example 1, Step 1. The substance was used directly in Step 2.

[0456] LCMS (Method A): 1.929 min. 2.010 minutes, MS:ES+407.0(M+1).

[0457] Step 2: (2-Chloro-4,6-dihydroxyphenyl)(4-(methylamino)isoindorin-2-yl) [ka] The compound in question was prepared from (2-chloro-4,6-bis(methoxymethoxy)phenyl)(4-(methylamino)isoindorin-2-yl)methanone (Step 1) and 4M HCl in dioxane by a method similar to that of Step 2 in Example 4.

[0458] 1 H NMR(DMSO-d6,400MHz):δ 2.62 and 2.72 (2 doublets, J=4.8Hz, 3H), 4.23-4.46 (m, 2H), 4.55 (s, 1H), 4.68 (s, 1H), 5.37-5.52 (m ,1H,D2O exchangeable),6.34-6.40(m,3H),6.46-6.57(m,1H),7.07-7.14(m,1H),9.97(s,2H,D2O exchangeable).

[0459] LCMS (Method A): 1.469 min. MS:ES+318.9(M+1).

[0460] Analytical HPLC (Method D): 5.105 min.

[0461] Step 3: (E)-N-(2-(2-chloro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] The compound in question was prepared from (E)-4-(dimethylamino)buta-2-enoic acid (CAS: 848133-35-7) and (2-chloro-4,6-dihydroxyphenyl)(4-(methylamino)isoindorin-2-yl)methanone (Step 2) by a method similar to that of Example 1 and Step 2.

[0462] high temperature 1 H NMR (D2O exchange, DMSO-d6, 400MHz, 349K): 2.09 (s, 6H), 3.09 (s, 2H), 3.22 and 3.45 (2 singlets, 3H), 4.31- 4.63(m,3H),4.83(s,1H),5.80(s,1H),6.31-6.39(m,2H),6.55-6.70(m,1H),7.17-7.44(m,3H).

[0463] LCMS (Method A): 1.045 min. MS:ES+430.0(M+1).

[0464] Analytical HPLC (Method D): 3.73 min.

[0465] Example 12: (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3,3-dimethylindoline-5-carbonyl)isoindoline-4-yl)-N-methylbuta-2-enamide [ka] To a solution of 6-hydroxy-3,3-dimethylindoline-5-carboxylic acid (intermediate R) (0.07 g, 0.33 mmol, 1 equivalent) in DMF (0.7 mL), EDC.HCl (0.096 g, 0.50 mmol, 1.5 equivalents) and HOAT (0.045 g, 0.33 mmol, 1 equivalent) were added, and the mixture was stirred at room temperature for 15 minutes. (E)-4-(dimethylamino)(isoindoline-4-yl)methylbuta-2-enamide hydrochloride (intermediate S) (0.15 g, 0.50 mmol, 1.5 equivalents) and NMM (0.17 g, 1.69 mmol, 5 equivalents) were added, and stirring was continued at room temperature for 2 hours. The resulting mixture was diluted with water (20 mL) to precipitate the solid. The solid was recovered by filtration, washed with water (3 × 5 mL), and purified by preparative HPLC after elution with 0.05% HCl / acetonitrile in water. The product fraction was freeze-dried to obtain the labeled compound (0.012 g, yield: 6%).

[0466] 1 H NMR (DMSO-d6, 400MHz, D2O exchange): 1.28 (s, 6H), 2.62 (s, 6H), 3.20 (bs, 3H), 3.55 (bs, 2H), 3.74-3.93 (m, 2H), 4.60-4.64 (m, 1H) ,4.80-4.87(m,3H),6.04(d,J=15.2Hz,1H),6.53(bs,1H),6.71(s,1H),7.18(bs,1H),7.20-7.26(m,1H),7.43-7.44(m,2H).

[0467] LCMS (Method A): 1.100 min, MS: ES+449.1(M+1).

[0468] Analytical HPLC (Method-D): 3.580 min.

[0469] Preparative HPLC purification method: Chromatographic separation and isolation were performed using a Shimadzu LC20AP with a UV detector. The column used was a Shim-Pack GIST C18 (250 mm × 20 mm × 5 μm). The compounds were eluted using mobile phase A: 0.05% HCl in water and mobile phase B: acetonitrile, with gradients of T=0.01 min (90% A, 10% B), T=17.00 min (74% A, 26% B), T=17.01 min (2% A, 98% B), T=19.00 min (2% A, 98% B), T=19.01 min (90% A, 10% B), and T=23 min (90% A, 10% B). Flow rate = 20 mL / min, analysis time 23 minutes.

[0470] Example 13.1: (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide [ka] 4,6-dihydroxy-2,3-dimethylbenzoic acid (intermediate K) (150 mg, 0.41 mmol, 1.00 equivalent), HOBT (95 mg, 0.62 mmol, 1.5 equivalent), EDC (118 mg, 0.62 mmol, 1.5 equivalent), and (E)-4-(dimethylamino)-N-(isoindorin-4-yl)methylbuta-2-enamide dihydrochloride (intermediate V1-1) (178 mg, 0.54 mmol, 1.3 equivalent) were mixed in DMF (4.6 mL) and DIPEA (0.29 mL, 1.65 mmol, 4.00 equivalent) was added. The reaction mixture was stirred at room temperature for 48 hours. MP carbonate resin (3.0 equivalent) was added and the mixture was stirred using a shaker for 1 hour. The resulting mixture was filtered through hydrophobic frit and concentrated under reduced pressure. The crude substance was purified by preparative HPLC (preparative-LC-2 method) to obtain the indicated compound as formate (12 mg, 6.4%). 1H NMR(400MHz,DMSO)δ 1.93-2.03(m,12H),2.77-2.89(m,2H),3.08-3.23(m,3H),4.59-4.88(m,2H),5.66-5.80(m,1H),6.30- 6.32(m,1H),6.60-6.73(m,1H),7.19-7.23(m,1H),7.28-7.33(m,2H),7.37-7.46(m,2H),8.21(s,1H).

[0471] LCMS (LC-Method 1): 2.66 min, MS: ES+424.2(M+1)

[0472] The compounds in the examples shown below (Table Ex13) were prepared from the indicated intermediates using a method similar to that of Example 13.1.

[0473] [Table 4]

[0474] [Table 5]

[0475] [Table 6]

[0476] [Table 7]

[0477] [Table 8]

[0478] [Table 9]

[0479] [Table 10]

[0480] Table 11

[0481] Table 12

[0482] Table 13

[0483] Table 14

[0484] Table 15

[0485] Table 16

[0486] Table 17

[0487] Table 18

[0488] Table 19

[0489] Table 20

[0490] Example 14: N-[2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl]-N-[2-(4-pyridyl)ethyl]propa-2-enamide [ka] To a stirred solution of 2,4-dihydroxy-5-methylbenzoic acid (30 mg, 0.18 mmol, 1.5 equivalents) in DCM (0.50 mL), EDC (34 mg, 0.18 mmol, 1.5 equivalents) and DIPEA (0.081 mL, 0.47 mmol, 4.0 equivalents) were added under an inert atmosphere. In separate round-bottom flasks, a solution of N-isoindolin-4-yl[2-(4-pyridyl)ethyl]prop-2-enamidobistrifluoroacetate (intermediate W2-1) (62 mg, 0.12 mmol, 1.0 equivalent) in DMF (1.0 mL) was combined with DIPEA (0.041 mL, 0.23 mmol, 2.0 equival...

Claims

1. The following structural formula (I): 【Chemistry 1】 (In the formula, R ２ These are hydrogen, halo, cyano, hydroxy, (1-6C) alkyl, (1-6C) alkoxy, or (1-6C) haloalkyl, R ３ These are hydrogen, halo, cyano, hydroxy, (1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy, amino-(1-6C)alkyl, or (1-6C)haloalkyl. R ４ This includes hydrogen, halo, cyano, hydroxy, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) haloalkyl, (1-6C) haloalkoxy or NR ４Ａ R ４Ｂ And R ４Ａ and R ４Ｂ These are independently selected from hydrogen or (1-6C) alkyl groups. R ５ is hydrogen, halo, cyano, hydroxy, (1-6C) alkyl, (1-6C) alkoxy or (1-6C) haloalkyl, or R ４ and R ５ are linked, together with the atoms to which they are attached, such that they form a 4- to 6-membered heterocyclyl or heteroaryl, any 4- to 6-membered heterocyclyl or heteroaryl being optionally substituted by one or more R Ａ groups, each R Ａ being independently selected from halo, cyano, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy or (1-6C)haloalkyl, X is N, CH, or CR ６ And R ６ These are halo, cyano, (1-6C) alkyl, or (1-6C) haloalkyl, Y １ is, -CH ２ -, C(=O)- or -CHR Ｂ And R Ｂ Halo, cyano, methyl, methoxy, CF ３ , -OCF ３ Or selected from hydroxymethyl, Y ２ is, -CH ２ -, -C(=O)-, -CHR Ｃ -ien-CH ２ -CH ２ -ien-CH ２ - CHR Ｃ - or - CHR Ｃ -CH ２ - and R Ｃ Halo, cyano, methyl, methoxy, CF ３ , -OCF ３ Or selected from hydroxymethyl, A １ N, CH, CR ７ or CR １２ Selected from, A ２ N, CH, CR ７ or CR １２ Selected from, A ３ is N, CH or CR １３ Selected from, A ４ is N, CH or CR １４ Selected from, however, A １ A ２ A ３ Or A ４ Only one or two of these can be N, and A １ and A ２ One of them is CR ７ And, R ７ This is expressed by the following formula (IA) or (IB): 【Chemistry 2】 It is the basis of, 【Transformation 3】 is, A １ Or A ２ It shows the connection point to, R ８Ａ These are hydrogen, (1-6C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, heterocyclyl-(1-4C)alkyl, heteroaryl-(1-4C)alkyl, or 8-12 membered carbocyclyl. R ８Ａ Each alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and each phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy. R ８Ａ Any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyrillic moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and any phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy. R ８ This is represented by the following formula (IA-I) or (IA-II): 【Chemistry 4】 It is the basis of, 【Transformation 5】 This indicates a connection point. R ８Ｂ and R ８Ｄ These include hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl and -C(O)NR ８Ｆ R ８Ｇ Each of the groups consisting of R is independently selected, ８Ｆ and R ８Ｇ These are independently selected from hydrogen or (1-4C) alkyl groups. R ８Ｂ and / or R ８Ｄ Any alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R ８Ｂ and / or R ８Ｄ Each cycloalkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R ８Ｃ This is selected from hydrogen, halo, (1-6C)alkyl, (1-6C)alkoxy, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, di[(3-6C)cycloalkyl]amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, heterocyclyl-(1-4C)alkyl, or heteroaryl-(1-4C)alkyl. R ８Ｃ Any alkyl moiety present is a halo, hydroxy, cyano, oxo, (1-6C) alkoxy, or NR. ８ＣＡ R ８ＣＢ (Here, R ８ＣＡ and R ８ＣＢ Each is optionally substituted with one or more substituents independently selected from hydrogen and (1-6C)alkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and each phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy. R ８Ｃ Any alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present in is a halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, NR ８ＣＣ R ８ＣＤ (Here, R ８ＣＣ and R ８ＣＤ Each is optionally substituted with one or more substituents independently selected from hydrogen and (1-6C)alkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl, and each phenyl or 4-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy, or R ８Ａ and R ８Ｄ These atoms, along with the atoms to which they are bonded, are linked so that they form 4-6 membered heterocyclines, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) haloalkyl, (3-6C) cycloalkoxy, phenyl, or 4-6 membered heterocyclines. R ８Ｅ This is selected from the group consisting of hydrogen, halo, (1-4C)alkyl, (3-6C)cycloalkyl, and (3-6C)cycloalkyl-(1-2C)alkyl. R ８Ｅ Any alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkoxy, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R ８Ｅ Each cycloalkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (3-6C)cycloalkoxy, phenyl, or 4-6 membered heterocyclyl. R １２ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy, and (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R １２ is, -(CHR ｐ ) ｆ -Z １２ And, R ｐ is hydrogen or methyl, f 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 4-6 member heterocyclyl, 5- or 6-member heteroaryl, -(CHR ｑ ) ｅ -(3-7C)cycloalkyl, -(CHR ｑ ) ｅ -phenyl, -(CHR ｑ ) ｅ -[4-6 member heterocyclyl] or -(CHR ｑ ) ｅ -[5- or 6-member heteroaryl], and R ｑ is hydrogen or methyl, and e is either 0 or 1. R ２１ and R ２２ These are hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR ｒ ) ｄ -(3-7C)cycloalkyl, -(CHR ｒ ) ｄ -phenyl, -(CHR) ｒ ) ｄ - [4-6 member heterocycline] or - (CHR) ｒ ) ｄ - Independently selected from [5- or 6-membered heteroaryls], R ｒ is hydrogen or methyl, and d is either 0 or 1, or R ２１ and R ２２ They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R ２３ is hydrogen or (1-2C) alkyl, R ２４ (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR ｓ ) ｃ -(3-7C)cycloalkyl, -(CHR ｓ ) ｃ -phenyl, -(CHR) ｓ ) ｃ - [4-6 member heterocycline] or - (CHR) ｓ ) ｃ - [5 or 6-membered heteroaryl], R ｓ is hydrogen or methyl, and c is either 0 or 1, R ２０ , R ２１ , R ２２ , R ２３ Or R ２４ Each of or R ２１ and R ２２ When they are connected, each of the rings formed has one or more R Ｄ It is optionally replaced by R １３ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R １３ is, -(CHR ｏ ) ｈ -Z １３ And, R ｏ is hydrogen or methyl, h is 0 or 1, and Z １３ is, -OR ２５ , -NR ２６ R ２７ , -C(O)NR ２６ R ２７ or -NR ２８ C(O)R ２９ And, R ２５ (1-4C) alkyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR ｎ ) ｉ -(3-7C)cycloalkyl, -(CHR ｎ ) ｉ -phenyl, -(CHR) ｎ ) ｉ - [4-6 member heterocycline] or - (CHR) ｎ ) ｉ - [5 or 6-membered heteroaryl], R ｎ is hydrogen or methyl, and i is either 0 or 1, R ２６ and R ２７ These are hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR ｍ ) ｊ -(3-7C)cycloalkyl, -(CHR ｍ ) ｊ -phenyl, -(CHR) ｍ ) ｊ - [4-6 member heterocycline] or - (CHR) ｍ ) ｊ - Independently selected from [5- or 6-membered heteroaryls], R ｍ is hydrogen or methyl, and j is either 0 or 1, or R ２６ and R ２７ They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R ２８ is hydrogen or (1-2C) alkyl, R ２９ (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, carbon-linked 4-6 member heterocyclyl, 5 or 6 member heteroaryl, -(CHR ｌ ) ｋ -(3-7C)cycloalkyl, -(CHR ｌ ) ｋ -phenyl, -(CHR) ｌ ) ｋ - [4-6 member heterocycline] or - (CHR) ｌ ) ｋ - [5 or 6-membered heteroaryl], R ｌ is hydrogen or methyl, and k is either 0 or 1. R ２５ , R ２６ , R ２７ , R ２８ Or R ２９ Each of or R ２６ and R ２７ When they are connected, each of the rings formed has one or more R Ｄ It is optionally replaced by R １４ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R １４ is, -(CHR ｋ ) ｍ -Z １４ And, R ｋ is hydrogen or methyl, 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 And, R ３０ (1-4C) alkyl, (3-7C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR ｊ ) ｏ -(3-7C)cycloalkyl, -(CHR ｊ ) ｏ - [4-6 member heterocycline] or - (CHR) ｊ ) ｏ - [5 or 6-membered heteroaryl], R ｊ is hydrogen or methyl, and o is either 0 or 1. R ３１ and R ３２ These are hydrogen, (1-6C) alkyl, (2-6C) alkanoyl, (3-7C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR ｉ ) ｐ -(3-7C)cycloalkyl, -(CHR ｉ ) ｐ - [4-6 member heterocycline] or - (CHR) ｉ ) ｐ - Independently selected from [5- or 6-membered heteroaryls], R ｉ is hydrogen or methyl, and p is either 0 or 1, or R ３１ and R ３２ They are linked together with the nitrogen atoms to which they are bonded, so as to form a 4- to 6-membered heterocycle. R ３３ is hydrogen or (1-2C) alkyl, R ３４ (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, carbon-linked 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, -(CHR ｈ ) ｑ -(3-7C)cycloalkyl, -(CHR ｈ ) ｑ - [4-6 member heterocycline] or - (CHR) ｈ ) ｑ - [5 or 6-membered heteroaryl], R ｈ is hydrogen or methyl, and q is either 0 or 1, R ３０ , R ３１ , R ３２ , R ３３ Or R ３４ Each of or R ３１ and R ３２ When they are connected, each of the rings formed has one or more R Ｄ It is optionally replaced by Each R Ｄ is an oxo, halo, cyano, hydroxy, (1-4C) alkyl or group: -L １ -X １ -Q １ (In the formula, L １ It does not exist, or it is an (1-2C) alkylene. X １ It does not exist, or -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) ０～２ -, -C(O)-N(R １５ )-,-N(R １５ )-C(O)-,-NR １５ -, -N(R １５ )-C(O)-NR １５ -, -SO ２ N(R) １５ ) - or - N (R １５ ) SO ２ - Selected from the group consisting of, each R １５ is independently selected from hydrogen or (1-4C) alkyl, and Q １ (Selected from the group consisting of hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or (3-6C) cycloalkyl) (Selected independently from the group consisting of) Compounds containing or pharmaceutically acceptable salts, hydrates, or solvates thereof.

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

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

4. R ４ This includes hydrogen, halo, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy or NR ４Ａ R ４Ｂ And R ４Ａ and R ４Ｂ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is independently selected from hydrogen or (1-4C) alkyl.

5. R ５ This includes hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl (e.g., n-propyl or i-propyl), butyl (e.g., n-butyl, i-butyl or t-butyl), methoxy or CF ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

6. R ４ and R ５ They are linked together with the atoms to which they are bonded, so that they form a five-membered heterocycline or a five-membered heteroaryl containing one or two nitrogen atoms, and each five-membered heterocycline or five-membered heteroaryl contains one, two or three R Ａ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is optionally substituted by [the specified compound].

7. Each R Ａ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, independently selected from fluoro, chloro, hydroxy, oxo, methyl, or ethyl.

8. X is N, CH, C-Cl, CF, C-Br, C-CN, C-CH ３ C-CH ２ CH ３ C-CH ２ F, C-CHF ２ or C-CF ３ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

9. Y １ is, -CH ２ - and / or Y ２ is, -CH ２ - or - CH ２ -CH ２ - The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. A １ N, CH, CR ７ or CR １２ Selected from, A ２ N, CH, CR ７ or CR １２ Selected from, A ３ is N, CH or CR １３ Selected from, A ４ is N, CH or CR １４ Selected from, however, A １ A ２ A ３ Or A ４ Only one of them can be N, A １ and A ２ One of them is CR ７ And, A ４ CR １４ If A ３ CR １３ It is not possible, and A ３ CR １３ If A ４ CR １４ A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which cannot be.

11. R ８Ａ These are hydrogen, (1-4C) alkyl, hydroxy-(1-2C)alkyl, (1-2C)alkoxy-(1-2C)alkyl, 4-6 member cycloalkyl, aryl, 4-6 member heterocyclyl, heteroaryl, 4-6 member cycloalkyl-(1-2C)alkyl, aryl-(1-2C)alkyl, 4-6 member heterocyclyl-(1-2C)alkyl, heteroaryl-(1-2C)alkyl, or 8-10 member carbocyryl. R ８Ａ Any alkyl moiety present is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkoxy, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl. R ８Ａ Any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyrillic moiety present in is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, oxo, (1-3C)alkyl, (1-3C)alkoxy, (1-3C)haloalkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl compounds, as described in any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. R ８Ａ These are hydrogen, methyl, ethyl, propyl (e.g., i-propyl or n-propyl), hydroxyethyl, methoxyethane, phenyl, piperidine, pyrrolidine, phenyl-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, pyrazole-(1-2C)alkyl, pyridine-(1-2C)alkyl, morpholine-(1-2C)alkyl, tetrahydropyran-(1-2C)alkyl, or dihydroindene. R ８Ａ Each alkyl moiety present is optionally substituted with one substituent selected from chloro, fluoro, hydroxy, methoxy, or phenyl. R ８Ａ A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein any alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, or carbocyrillic moiety present is optionally substituted with one substituent selected from chloro, fluoro, hydroxy, methyl, methoxy, or phenyl.

13. R ８Ｂ and R ８Ｄ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is independently selected from the group consisting of hydrogen, fluoro, chloro, or methyl.

14. R ８Ｃ This is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, [(1-4C)alkyl]amino, di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl, [(1-4C)alkyl]amino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, [(1-4C)alkyl][(3-6C)cycloalkyl]amino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, 4-6 membered cycloalkyl-(1-4C)alkyl, aryl-(1-4C)alkyl, 4-6 membered heterocyclyl-(1-4C)alkyl, or heteroaryl-(1-4C)alkyl. R ８Ｃ Any alkyl moiety present is a halo, hydroxy, cyano, oxo, (1-3C) alkoxy, or NR. ８ＣＡ R ８ＣＢ (Here, R ８ＣＡ and R ８ＣＢ Each is optionally substituted with one or more substituents independently selected from hydrogen and (1-3C)alkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl, and each phenyl or 5-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4-6C)cycloalkyl, or (4-6C)cycloalkoxy. R ８Ｃ Any alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl moiety present in is a halo, hydroxy, cyano, oxo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, NR ８ＣＣ R ８ＣＤ (Here, R ８ＣＣ and R ８ＣＤ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is optionally substituted with one or more substituents independently selected from hydrogen and (1-4C)alkyl, (4-6C)cycloalkoxy, phenyl, or 5-6 membered heterocyclyl, and each phenyl or 5-6 membered heterocyclyl is optionally further substituted with one or more substituents independently selected from halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)alkoxy, (4-6C)cycloalkyl, or (4-6C)cycloalkoxy.

15. R ８Ｃ is hydrogen, methyl, -CH ２ -NR ８Ｃ１ R ８Ｃ２ ien-CH ２ -N(R) ８Ｃ１ ) (3C) Cycloalkyl, NR ８Ｃ１ R ８Ｃ２ Selected from (1-2C)alkoxy-(1-2C)alkyl, 4-6 member nitrogen-containing heterocyclyl-(1-2C)alkyl, or nitrogen-containing heteroaryl-(1-2C)alkyl, R ８Ｃ１ and R ８Ｃ２ These are independently selected from hydrogen, methyl, and ethyl. R ８Ｃ Any alkyl moiety present in is fluoro, chloro, hydroxy, methoxy, or NH ２ It is optionally substituted with one or two substituents independently selected from the original compound. R ８Ｃ Any alkoxy, heterocyclyl, or heteroaryl moiety present in is fluoro, chloro, hydroxy, methyl, methoxy, or NH ２ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, optionally substituted with one or two substituents independently selected from the compound.

16. R ８ｃ is hydrogen, methyl, -CH ２ -NH ２ ien-CH ２ -NMe ２ ien-CH ２ -NET ２ ien-CH ２ -N(Me)Et, CH ２ -N(Me)cyclopropyl, -NH ２ , -NMe ２ , selected from (1-2C)alkoxy-(1-2C)alkyl, pyrrolidine-(1-2C)alkyl, morpholine-(1-2C)alkyl or azetidine-(1-2C)alkyl, R ８Ｃ A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein any alkoxy, heterocyclyl, or heteroaryl moiety present is optionally substituted with two substituents independently selected from fluoro, chloro, hydroxy, or methyl.

17. R ８Ａ and R ８Ｄ They are linked together with the atoms to which they are bonded, so that they form a five-membered heterocycline. Any five-membered heterocyclyl can be classified as fluoro, chloro, hydroxy, methyl, methoxy, CHF ２ or CF ３ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, optionally substituted with one or two substituents independently selected from the compound.

18. R １２ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R １２ is, -(CHR ｐ ) ｆ -Z １２ And, R ｐ is hydrogen or methyl, f is 0 or 1, and Z １２ is, -OR ２０ or -NR ２１ R ２２ And, R ２０ These are (1-3C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl. R ２１ and R ２２ Each of these is independently selected from hydrogen, (1-2C) alkyl, (2-3C) alkanoyl, (4-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, or R ２１ and R ２２ They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R ２０ , R ２１ Or R ２２ Each of or R ２１ and R ２２ Each ring formed when they are connected has one or two R Ｄ A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is optionally substituted with.

19. R １３ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R １３ is, -(CHR ｏ ) ｈ -Z １３ And, R ｏ is hydrogen or methyl, h is 0 or 1, and Z １３ is, -OR ２５ or -NR ２６ R ２７ And, R ２５ These are (1-3C) alkyl, (3-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl. R ２６ and R ２７ Each of these is independently selected from hydrogen, (1-2C) alkyl, (2-3C) alkanoyl, (4-6C) cycloalkyl, phenyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, or R ２６ and R ２７ They are linked together with the nitrogen atom to which they are bonded, so that they form a 4-6 member heterocycline. R ２５ , R ２６ Or R ２７ Each of or R ２６ and R ２７ Each ring formed when they are connected has one or two R Ｄ A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is optionally substituted with.

20. R １４ is selected from cyano, halo, (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl, and any (1-2C)alkyl, (1-2C)alkoxy or (3-6C)cycloalkyl is optionally substituted with one or more halo or (1-2C)alkoxy, or R １４ is, -(CHR ｋ ) ｍ -Z １４ And, R ｋ is hydrogen or methyl, m is 0 or 1, and Z １４ is, -OR ３０ or -NR ３１ R ３２ And, R ３０ These are (1-3C) alkyl, (3-6C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl. R ３１ and R ３２ These are independently selected from hydrogen, (1-2C) alkyl, (2-3C) alkanoyl, (3-6C) cycloalkyl, carbon-linked 4-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, or R ３１ and R ３２ They are linked together with the nitrogen atoms to which they are bonded, so as to form a 4- to 6-membered heterocycle. R ３０ , R ３１ Or R ３２ Each of or R ３１ and R ３２ Each ring formed when they are connected has one or two R Ｄ A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which is optionally substituted with.

21. Each R Ｄ is an oxo, chloro, fluoro, cyano, hydroxy, methyl or group: -L １ -X １ -Q １ (In the formula, L １ It does not exist, or it is methylene. X １ It does not exist, or is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -NH- or NMe-, and Q １ (Selected from the group consisting of hydrogen, (1-2C) alkyl, (2-3C) alkenyl, (2-3C) alkynyl, or (3-6C) cycloalkyl) A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, independently selected from the group consisting of the above.

22. The aforementioned compound, (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(diethylamino)-N-((1-methyl-1H-pyrazole-4-yl)methyl)buta-2-enamide, (E)-4-(3,3-difluoropyrrolidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, ((E)-4-(3,3-difluoroazetidine-1-yl)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(pyrrolidine-1-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-morpholinbuta-2-enamide, N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)isoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-4-fluoro-2-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-benzyl-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)acrylamide, N-benzyl-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)acrylamide, (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-phenethylbuta-2-enamide, (E)-N-(2-(2-chloro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3,3-dimethylindoline-5-carbonyl)isoindoline-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-hydroxyethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(pyridine-4-ylmethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-4-yl)ethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-2-yl)ethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-3-yl)ethyl)buta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(pyridine-2-yl)ethyl)buta-2-enamide, E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-(2-methoxyethyl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-chloro-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-1H-indole-5-carbonyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(5-bromo-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-(trifluoromethyl)benzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-cyano-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-(trifluoromethyl)benzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-benzoylisoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-2-methoxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2-(difluoromethyl)-4-hydroxybenzoyl)isoindoline-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2-chloro-4-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-1H-indazole-5-carbonyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(4-(difluoromethyl)-2-hydroxybenzoyl)isoindoline-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-fluoro-2,4-dihydroxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxybenzo[d]isoxazole-5-carbonyl)isoindoline-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(4-amino-2-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-ethyl-2,4-dihydroxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-4-(difluoromethoxy)-6-hydroxy-2-methylbenzoyl)isoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(4-(difluoromethoxy)-2-hydroxy-5-methylbenzoyl)isoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-(tert-butyl)-4-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-(trifluoromethyl)benzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-4-hydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-[2-(2,4-dihydroxy-5-methyl-benzoyl)isoindorin-4-yl]-N-[2-(4-pyridyl)ethyl]proper-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-N-(2-(1-methylpyrrolidine-3-yl)ethyl)acrylamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)acrylamide, N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)acrylamide, (E)-N-[2-(2,4-dihydroxy-5-methyl-benzoyl)isoindoline-4-yl]-4-(dimethylamino)-N-indan-2-ylbuta-2-enamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-N-(2-morpholinoethyl)acrylamide, N-(2-(2,4-dihydroxy-6-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-[2-(2,4-dihydroxybenzoyl)isoindorin-4-yl]-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-fluoro-4-hydroxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-2-methylbenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-hydroxypicolinoyl)isoindorin-4-yl)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-methoxybenzoyl)isoindorin-4-yl)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-(trifluoromethyl)benzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-methoxybuta-2-enamide, 1-(2-(2,4-dihydroxy-5-methylbenzoyl)isoindoline-4-yl)-3-(2-(dimethylamino)ethylidene)pyrrolidine-2-one, N-(2-(2,4-dihydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpiperidine-4-yl)acrylamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-N-(2-methoxyethyl)acrylamide, N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(2-(5-(tert-butyl)-2,4-dihydroxybenzoyl)-5-chloroisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)isoindoline-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, (E)-N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(ethyl(methyl)amino)-N-methylbuta-2-enamide, (E)-N-(7-chloro-2-(2,4-dihydroxy-5-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(7-chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(5-chloro-2-(4,6-dihydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-ethylbuta-2-enamide, N-(2-(3-chloro-4,6-dihydroxy-2-methylbenzoyl)isoindorin-4-yl)-N-ethylacrylamide, N-(2-(3-chloro-2-fluoro-4,6-dihydroxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(2,4-dihydroxy-5-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)isoindorin-4-yl)-N-methylacrylamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-2,3-dimethyl-1H-indole-5-carbonyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-2-methyl-1H-indole-5-carbonyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(6-hydroxy-3-methyl-1H-indole-5-carbonyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-4-methoxy-5-methylbenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-(tert-butyl)-2-fluoro-6-hydroxy-5-(hydroxymethyl)benzoyl)isoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-(aminomethyl)-5-(tert-butyl)-6-fluoro-2-hydroxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-5-chloroisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(5-ethyl-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)isoindoline-4-yl)-N-methylacrylamide, N-(2-(5-ethyl-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(2-(3-(tert-butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-(tert-butyl)-2-fluoro-6-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)-5-methylisoindolin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(5-chloro-2-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-5-methylisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(5-chloro-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(6-hydroxy-3,3-dimethyl-2-oxoindoline-5-carbonyl)isoindoline-4-yl)-N-methylacrylamide, N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridine-3-yl)-N-methylacrylamide, N-(7-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylacrylamide, N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylacrylamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-4-fluoro-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)acrylamide, (E)-N-(2-(3-chloro-6-hydroxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(6-(5-(tert-butyl)-2-hydroxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(5-chloro-2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(5-chloro-2-(4-hydroxy-3-isopropylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-(2-(dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-inamide, (E)-N-(5-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-fluoro-4-hydroxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(2-(5-(tert-butyl)-2-hydroxy-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(3-chloro-2-fluoro-6-hydroxy-4-methoxybenzoyl)isoindorin-4-yl)-N-methylacrylamide, N-(5-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-4-(dimethylamino)-N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5-methylisoindoline-4-yl)-N-methylbuta-2-enamide, N-(2-(4-fluoro-2-hydroxy-5-isopropylbenzoyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-(2-(dimethylamino)ethoxy)-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-2,6-naphthyridine-3-yl)-N-methylacrylamide, (E)-N-(7-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylbuta-2-enamide, N-(7-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylacrylamide, N-(7-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine-2-yl)-N-methylacrylamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpiperidine-4-yl)acrylamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-5-methylisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(2-(4,6-dihydroxy-2,3-dimethylbenzoyl)-6-methylisoindoline-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylacrylamide, N-(2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpyrrolidine-3-yl)acrylamide, ((E)-N-(5-chloro-2-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindoline-4-yl)-4-(dimethylamino)buta-2-enamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)acrylamide, (E)-N-(2-(3-chloro-6-hydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, (E)-N-(7-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)-N-methylbuta-2-enamide, N-(7-chloro-2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)isoindorin-4-yl)-N-methylacrylamide, (E)-4-(dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-6-(2-(dimethylamino)ethoxy)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-inamide, (E)-N-(5-chloro-2-(3-chloro-4-hydroxy-2-methylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-N-(5-chloro-2-(4-hydroxy-2,3-dimethylbenzoyl)isoindorin-4-yl)-4-(dimethylamino)buta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, (E)-4-(dimethylamino)-N-(2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, N-(2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(1-methylpiperidine-4-yl)acrylamide, (E)-4-(dimethylamino)-N-(6-(2-hydroxy-5-isopropyl-4-methoxybenzoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, ((E)-4-(dimethylamino)-N-(6-(4-hydroxy-3-isopropylbenzoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-N-methylbuta-2-enamide, (E)-N-(2-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-methylbuta-2-enamide, N-(6-(3-chloro-6-hydroxy-4-methoxy-2-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)buta-2-inamide A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from any one of the above.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, mixed with a pharmaceutically acceptable diluent or carrier.

24. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition according to claim 23, for use in therapeutic purposes.

25. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition according to claim 23, (i) Use in the treatment of cancer, (ii) Use in the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with another anticancer agent (e.g., a chemotherapeutic agent, an immune checkpoint inhibitor, an immunostimulant, or a DNA damage repair modifier), (iii) Use in the treatment of triplet repeat disease Compounds or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for the purpose of [unspecified purpose].

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