Heterocyclic compounds useful for treating ERK5-mediated diseases

Abstract

The present invention relates to compounds of formula (I) as shown below, wherein R1, R2, R3, X1, L and Q are each as defined herein, which function as degraders of ERK5 kinase. The compounds are useful for treating: fibrotic diseases; proliferative conditions, such as cancer; diabetes; pain; and / or central nervous system (CNS) disorders. [Formula 1] JPEG2025508435000155.jpg74170

Description

[Technical field]

[0001] The present invention relates to several compounds that function as proteolysis targeting chimeras (PROTACs) against ERK5 kinase. The present invention also relates to methods for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions associated with ERK5 activity. [Background technology]

[0002] The extracellular signal-regulated kinase 5 (ERK5, also known as big MAP kinase 1, BMK1) protein encoded by the MAPK7 gene is a member of the mitogen-activated protein kinase (MAPK) family. The ERK5 signaling cascade can be activated by environmental stress, mitogens and cytokines. These stimuli activate MEKK2 and MEKK3, which can phosphorylate and activate MEK5. Upon activation, MEK5 phosphorylates the TEY motif within the activation loop of the ERK5 kinase domain, thereby leading to ERK5 activation (for reviews see Hoang et al, 2017. Cancer letters; Drew et al, 2012. Biochimica et Biophysica Acta; Nithianandarajah-Jones et al, 2012. Cellular Signalling).

[0003] ERK5 is a MAPK with unique functions within the MAPK family, namely, nonkinase functions in cell cycle progression and transcriptional activation. ERK5 is upregulated in almost all cancers. MEK5 / ERK5 upregulation or hyperactivation correlates with poorer outcomes and therapy resistance in several cancers, including mesothelioma, osteosarcoma, triple-negative breast cancer, esophageal cancer, prostate cancer, and lung cancer. ERK5 has little homeostatic function, making it an attractive drug target because it is a stress kinase that is "switched on" in pathology.

[0004] To date, approaches to reduce ERK5 kinase activity have focused on kinase inhibition. However, this approach has several problems. It has been found that kinase inhibition can cause paradoxical activation of ERK5. Kinase inhibitors are also non-specific and have activity against proteins necessary for health, such as BRD4. Furthermore, certain iterations of ERK5 kinase inhibitors cannot recapitulate the phenotype of ERK5 reduction (genetic / siRNA). This is especially true for immunological effects. This is because kinase inhibitors cannot inhibit all aspects of ERK5 function, i.e., kinase and non-kinase-dependent functions.

[0005] There is a need for alternative methods to reduce ERK5 activity without inhibition, for example compounds that affect all aspects of ERK5 function (kinase and non-kinase dependent) via pharmacological approaches and can recapitulate the strong anti-cancer phenotype of ERK5 reduction (genetic / siRNA). One such approach involves degradation.

[0006] It is an object of the present invention to provide compounds that degrade ERK5 kinase. Summary of the Invention

[0007] In one aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0008] In another aspect, the present invention provides a pharmaceutical composition as defined herein comprising a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, and one or more pharma- ceutically acceptable excipients.

[0009] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0010] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition, suitably the proliferative condition is cancer.

[0011] In another aspect, the present invention provides a method for producing a method of making a semiconductor device comprising: a) fibrotic diseases, e.g., wound healing disorders, pulmonary fibrosis, b) Inflammatory diseases, e.g., psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) Pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of

[0012] In another aspect, the present invention relates to a method for treating cancer, e.g., triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, e.g., systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, e.g., cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, e.g., Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; bone There is provided a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of myelodysplastic syndromes, ischemic injury associated myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0013] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer. In a particular embodiment, the cancer is selected from triple-negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, or squamous cell carcinoma.

[0014] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a central nervous system (CNS) disorder. In a particular embodiment, the central nervous system (CNS) disorder is Parkinson's disease or dementia.

[0015] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in degrading or reducing the amount of ERK5 kinase.

[0016] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a proliferative condition.

[0017] In another aspect, the present invention provides a method for producing a method of making a semiconductor device comprising: a) fibrotic diseases, e.g., wound healing disorders, pulmonary fibrosis, b) Inflammatory diseases, e.g., psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) Pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia In another aspect, there is provided the use of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of

[0018] In another aspect, the present invention relates to a method for treating cancer, such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, such as Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerular nephropathy. myelodysplastic syndromes, ischemic injury associated myocardial infarction, stroke and reperfusion injury, cardiac arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood disorders such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic disorders such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0019] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of cancer, suitably the medicament for use in the treatment of human cancer.

[0020] In another aspect, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in degrading, or reducing the amount of, ERK5 kinase.

[0021] In another aspect, the present invention provides a method of degrading ERK5 in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0022] In another aspect, the present invention provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0023] In another aspect, the present invention provides a method for treating a patient in need of such treatment, comprising: a) fibrotic diseases, e.g., wound healing disorders, pulmonary fibrosis, b) Inflammatory diseases, e.g., psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) Pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia The present invention provides a method for treating a patient suffering from atopic dermatitis, the method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutical acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0024] In another aspect, the present invention relates to a method for treating: cancer, e.g., triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, e.g., systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, e.g., cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, e.g., Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, The present invention provides methods for treating retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic injury-related myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0025] In another aspect, the present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0026] In another aspect, the present invention provides a method of treating cancer in a patient in need of such treatment, comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0027] The present invention further provides a method of synthesizing a compound defined herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0028] In another aspect, the present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, obtainable by, or obtained directly by, a synthetic process as defined herein.

[0029] In another aspect, the present invention provides novel intermediates, as defined herein, suitable for use in any one of the synthetic methods as described herein.

[0030] Any preferred, suitable, or optional feature of one particular embodiment of the invention may also be a preferred, suitable, or optional feature of other embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] [Definition] Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0032] It is to be understood that references to "treating" or "treatment" include prevention as well as the alleviation of established symptoms of a condition. "Treating" a condition, disorder, or condition or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition as they occur in a person who may be afflicted by or predisposed to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence or at least one of its clinical or subclinical symptoms (in the case of maintenance treatment), or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0033] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity as well as the age, weight, etc. of the mammal to be treated.

[0034] "Alkyl" as used herein includes straight and branched chain alkyl groups. Reference to a particular alkyl group, e.g., "propyl", is specific for the straight chain version only, and reference to a particular branched chain alkyl group, e.g., "isopropyl", is specific for the branched chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and t-butyl. Similar rules apply to other groups, e.g., "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0035] The terms "(m-nC)" or "(m-nC) group" used alone or as a prefix, refer to any group having from m to n carbon atoms.

[0036] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that serves to position and connect two other chemical groups. "(1-6C)alkylene" means a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

[0037] "(2-6C)alkenylene" means a linear divalent hydrocarbon group of 2 to 6 carbon atoms or a branched divalent hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond, such as, for example, ethenylene, 2,4-pentadienylene, etc.

[0038] "(2-6C)alkynylene" means a linear divalent hydrocarbon group of 2 to 6 carbon atoms or a branched divalent hydrocarbon group of 3 to 6 carbon atoms containing at least one triple bond, such as, for example, ethynylene, propynylene, and butynylene.

[0039] "(3-8C)cycloalkyl" means a hydrocarbon ring containing 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl.

[0040] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-1-yl, or cyclooctenyl.

[0041] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0042] "Halo" or "halogeno" refers to fluoro, chloro, bromo and iodo.

[0043] "Heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocyclyl includes monovalent and divalent species. Monocyclic heterocyclic rings contain about 3 to 12 (suitably 3 to 7) ring atoms with 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms, suitably 7 to 12 member atoms in the ring. Bicyclic heterocyclic rings contain about 7 to about 17 ring atoms, suitably 7 to 12 ring atoms. Bicyclic heterocyclic ring(s) may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Exemplary sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. In the case of heterocycles containing sulfur, sulfur-oxidized heterocycles containing SO or SO groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide.Suitable values ​​for a 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. Particular heterocyclyl groups are saturated monocyclic 3-7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle can be linked to another group by any suitable atom, for example, by a carbon or nitrogen atom. However, reference to piperidino or morpholino herein refers to a piperidin-1-yl or morpholin-4-yl ring linked by the ring nitrogen.

[0044] "Bridged ring systems" refers to ring systems in which two rings share two or more atoms, e.g., as described in Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992. Bridged heterocyclyl ring systems include, for example, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0045] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0046] "Heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, e.g., 5- and 6-membered fused rings or a bicyclic structure formed from two 6-membered fused rings. Each ring can contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to 3 heteroatoms, more usually up to 2, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than 5.

[0047] Heteroaryl includes, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolyl, These include linyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other ring(s) is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0048] Five-membered heteroaryl groups include, for example, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0049] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0050] Bicyclic heteroaryl groups include, for example: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2 or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2 or 3 ring heteroatoms. It may be a group selected from:

[0051] Bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, by way of specific example and without limitation, benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0052] Bicyclic heteroaryl groups containing two six-membered fused rings include, by way of specific example and without limitation, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0053] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Heteroaralkyl groups include, for example, pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0054] "Aryl" means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In one particular embodiment, the aryl is phenyl.

[0055] "Aryl(1-6C)alkyl" means an aryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0056] The specification also uses some compound terms to describe groups that contain two or more functional groups. Such terms are understood by those of skill in the art. For example, heterocyclyl(m-nC)alkyl includes (m-nC)alkyl substituted with heterocyclyl.

[0057] "Optionally substituted" refers to groups, structures, or molecules that are substituted and groups, structures, or molecules that are not substituted. 1 "One / any CH, CH2, CH3 group or heteroatom (i.e., NH) in the group is optionally substituted" is R 1 Suitably it means that (any) one of the hydrogen radicals of the group is replaced by the associated specified group.

[0058] When optional substituents are 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.

[0059] "Compounds of the invention" means, both generically and specifically, the compounds disclosed herein.

[0060] [Compound according to the present invention] In one aspect, the present invention provides a compound having structural formula (I), as shown below: [ka] [In the formula, R1 is -S(O)2-(1-3C)alkyl; R2 is (1-4C)alkoxy; R3 is selected from hydrogen, fluoro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; X1 is N or CH; L is a group represented by the formula: [ka] (In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0 or 1; L1 is a (2-10C) alkylene linker or a group of formula -[CH2CH2-O] 1~3 -[CH2] 1~3 - a PEG chain having the formula: Y1 and Y2 are: Ethynylene group ( [ka] ); Ethylene group (-CH=CH-); -CH2-O-; -CH2-NH-; or -CH2-CH2- which together form: Q: [ka] (In the formula, [ka] represents the point of attachment to Y2 or group L; X2 is selected from -CH2- or -C(O)-; provided that Y1 and Y2 are ethynylene groups ( [ka] ), when taken together to form a -C(O)-, X2 is selected from -C(O)-, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0061] Particular compounds according to the invention include, for example, compounds of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof, in which, unless otherwise specified, each of R1, R2, R3, L, Q, and any associated substituents have any of the meanings defined above or in any of the following paragraphs (1) to (55): (1) R1 is -S(O)2-CH3. (2) R2 is (1-3C)alkoxy. (3) R2 is ethoxy. (4) R3 is selected from hydrogen, fluoro, or methyl. (5) R3 is hydrogen. (6) X1 is N. (7) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0 or 1; L1 is a (2-8C) alkylene linker or a group of formula -[CH2CH2-O] 1~3 -[CH2]1~2 - a PEG chain having the formula: Y1 and Y2 are: Ethynylene group ( [ka] ); -CH2-O-; -CH2-NH-; or -CH2-CH2- Together they form: (8) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0 or 1; L1 is a (2-8C) alkylene linker or a group of formula -[CH2CH2-O] 1~2 -[CH2] 1~2 - a PEG chain having the formula: Y1 and Y2 are: Ethynylene group ( [ka] ); -CH2-O-; -CH2-NH-; or -CH2-CH2- Together they form: (9) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0 or 1; L1 is a (2-8C)alkylene linker; Y1 and Y2 are: Ethynylene group ( [ka] ); -CH2-O-; -CH2-NH-; or -CH2-CH2- Together they form: (10) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0; L1 is a (2-8C) alkylene linker or a group of formula -[CH2CH2-O] 1~2 -[CH2] 1~2 - a PEG chain having the formula: Y1 and Y2 are: Ethynylene group ( [ka] ); -CH2-O-; -CH2-NH-; or -CH2-CH2- Together they form: (11) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0 or 1; L1 is a (2-8C) alkylene linker or a group of formula -[CH2CH2-O] 1~2 -[CH2] 1~2 - a PEG chain having the formula: Y1 and Y2 are: Ethynylene group ( [ka] ) Together they form: (12) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0; L1 is a (3-8C)alkylene linker; Y1 and Y2 are: Ethynylene group ( [ka] ); -CH2-O-; -CH2-NH-; or -CH2-CH2- Together they form: (13) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0; L1 is a (3-8C)alkylene linker; Y1 and Y2 are: Ethynylene group ( [ka] ) Together they form: (14) L is a group represented by the formula: [ka] [In the formula, [ka] represents the point of attachment to the N atom of the piperazine ring; [ka] represents the attachment point with Q; n is 0; L1 is a (5-8C)alkylene linker; Y1 and Y2 are: Ethynylene group ( [ka] ) Together they form: (15)L is: [ka] JPEG2025508435000043.jpg70170. (16)Q: [ka] wherein X2 is as defined herein. (17)Q: [ka] [In the formula, X2 is as defined herein.]

[0062] A heteroaryl or heterocyclyl group as defined herein is suitably a monocyclic heteroaryl or heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0063] Heteroaryl is suitably a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0064] Heterocyclyl groups are suitably 4-, 5- or 6-membered heterocyclyl rings containing 1, 2 or 3 heteroatoms selected from N, O or S. Most suitably, heterocyclyl groups are 5- or 6-membered rings containing 1, 2 or 3 heteroatoms selected from N, O or S, such as morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one).

[0065] The aryl group is suitably phenyl.

[0066] R1 is suitably as defined in paragraph (1), ie R1 is -S(O)2-CH3.

[0067] R2 is suitably as defined in paragraphs (2) and (3) above. Most suitably, R2 is as defined in paragraph (3), i.e., R2 is ethoxy.

[0068] R3 is suitably as defined in paragraphs (4) and (5) above. Most suitably, R3 is as defined in paragraph (5), i.e., R3 is hydrogen.

[0069] X1 is suitably as defined in paragraph (6), ie X1 is N.

[0070] L is suitably as defined in any one of paragraphs (7) to (15) above. More suitably, L is as defined in any one of paragraphs (10) to (15). Most suitably, L is as defined in paragraphs (14) or (15).

[0071] Q is suitably as defined in paragraph (16) or (17). Most suitably, Q is as defined in paragraph (17).

[0072] In a particular group of compounds according to the invention, R1 is as defined in paragraph (1), R2 is as defined in paragraph (3), R3 is as defined in paragraph (5) and X1 is as defined in paragraph (6); i.e. the compound has structural formula (Ia) (sub-definitions of formula (I)) as shown below: [ka] wherein L and Q are as defined herein.

[0073] In one embodiment of the compound of formula (Ia): L is as defined in any one of paragraphs (7) to (15) above; Q is as defined in paragraph (16) or (17) above.

[0074] In one embodiment of the compound of formula (Ia): L is as defined in any one of paragraphs (10) to (15) above; Q is as defined in paragraph (16) or (17) above.

[0075] In one embodiment of the compound of formula (Ia): L is as defined in any one of paragraphs (10) to (15) above; Q is as defined in paragraph (17) above.

[0076] In one embodiment of the compound of formula (Ia): L is as defined in paragraph (14) or (15) above; Q is as defined in paragraph (17) above.

[0077] Particular compounds according to the invention include any of the compounds exemplified in this application, or a pharma- ceutically acceptable salt or solvate thereof, in particular any of the following: 2-(2,6-dioxopiperidin-3-yl)-4-(5-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)pentyl)isoindoline-1,3-dione; 3-(4-(5-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(7-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hexyl)amino)isoindoline-1,3-dione; 3-(4-(3-(2-(2-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(8-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(9-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)non-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hexyl)oxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)butoxy)isoindoline-1,3-dione; 3-(4-(10-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)dec-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((8-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)octyl)oxy)isoindoline-1,3-dione; or a pharma- ceutically acceptable salt or solvate thereof.

[0078] The various functional groups and substituents forming the compound of formula (I) are usually selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More usually, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, for example, 550 or less.

[0079] Pharmaceutically acceptable salts of the compounds according to the invention are suitably, for example, sufficiently basic, such as acid-addition salts of the compounds according to the invention, for example, acid-addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methane sulfonate or maleic acid. Furthermore, pharma-ceutically acceptable salts of the compounds according to the invention that are sufficiently acidic are suitably 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 generate pharma-ceutically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0080] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and those that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates a plane of polarized light and can be named as dextrorotatory or levorotatory (i.e., (+) or (-)-isomer, respectively). Chiral compounds can exist as either enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0081] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include both individual enantiomers and their mixtures, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see those discussed in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). It is to be understood that the present invention encompasses all optical, diastereomeric and geometric isomers and mixtures thereof that have antiproliferative activity.

[0082] The present invention also includes compounds according to the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T) can be in any isotopic form; C is 12 C. 13 C, and 14 It can be in any isotopic form, including C; O is 16 O and 18 It may be in any isotopic form, including O, etc.

[0083] It is also to be understood that some compounds of formula (I) can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, etc. It is to be understood that the present invention encompasses all such solvated forms that possess antiproliferative activity.

[0084] It is also to be understood that some of the compounds of formula (I) may exhibit polymorphism, and that the invention encompasses all such forms which possess antiproliferative activity.

[0085] Compounds of formula (I) can exist in many different tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, compounds may exist in one of several tautomeric forms, only one of which will be described or shown in detail, while all others are encompassed by formula (I). Tautomeric forms include, for example, the keto, enol, and enolate forms for the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0086] [ka]

[0087] Compounds of formula (I) containing amine functional groups may also form N-oxides. References herein to compounds of formula (I) containing amine functional groups also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Particular examples of N-oxides are the N-oxides of tertiary amines or the nitrogen atoms of nitrogen-containing heterocycles. N-oxides may be formed by treatment of the corresponding amines with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), as described, for example, in Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 103. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent, such as dichloromethane.

[0088] The compounds of formula (I) can be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain a suitable group or substituent to which a property-modifying group can be attached. Prodrugs include, for example, in vivo cleavable ester derivatives that can be formed at a carboxy or hydroxy group in the compounds of formula (I) and in vivo cleavable amide derivatives that can be formed at a carboxy or amino group in the compounds of formula (I).

[0089] Thus, the present invention includes compounds of formula (I), as defined above, when available by organic synthesis and when available in the human or animal body as cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula (I) produced by organic synthetic means and also produced in the human or animal body as metabolism of a precursor compound, which is a compound of formula (I), such compounds may be synthetically produced compounds or metabolically produced compounds.

[0090] Pharmaceutically acceptable prodrugs of compounds of formula (I) are suitably based on sound medical judgment, such that they are free of undesirable pharmacological activity and free of undue toxicity and are suitable for administration to the human or animal body.

[0091] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology , Vol. 42 , p.309-396, edited by K.Widder, et al.(Academic Press, 1985); b)Design of Pro-drugs, edited by H.Bundgaard,(Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews , 8 , 1-38(1992); e) H. Bundgaard, et al. Journal of Pharmaceutical Sciences , 77 , 285(1988); f) N. Kakeya, et al., Chem.Pharm.Bull. ,32 , 692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0092] Pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are suitably, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula (I) containing a carboxy group are, for example, pharma- ceutically acceptable esters which are cleaved in the human or animal body to produce the parent acid. Pharmaceutically acceptable esters for carboxy suitably include C 1~6 Alkyl esters, such as methyl, ethyl, and tert-butyl, 1~6 Alkoxymethyl esters, such as methoxymethyl esters, C 1~6 Alkanoyloxymethyl esters, such as pivaloyloxymethyl esters, 3-phthalidyl esters, etc. 3~8 Cycloalkylcarbonyloxy-C 1~6 Alkyl esters, such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters, such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, and C 1~6 Alkoxycarbonyloxy-C 1~6 Alkyl esters include, for example, methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0093] The pharma- ceutically acceptable prodrug of the compound of formula (I) having a hydroxy group is suitably, for example, an in vivo cleavable ester or ether thereof. The in vivo cleavable ester or ether of the compound of formula (I) containing a hydroxy group is, for example, a pharma- ceutically acceptable ester or ether that is cleaved in the human or animal body to generate the parent hydroxy compound. The pharma- ceutically acceptable ester forming group for the hydroxy group suitably includes inorganic esters, for example, phosphate esters (including phosphoramidate cyclic esters), and the like. Further pharma- ceutically acceptable ester forming group for the hydroxy group is suitably, for example, C 1~10 Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1~10 Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C 1~6 ) 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents in the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1~4 Pharmaceutically acceptable ether forming groups for hydroxy groups suitably include α-acyloxyalkyl groups, for example acetoxymethyl and pivaloyloxymethyl groups.

[0094] Pharmaceutically acceptable prodrugs of compounds of formula (I) which have a carboxy group may suitably be, for example, an in vivo cleavable amide thereof, such as an amine, e.g. ammonia, etc., 1~4 Alkylamines, such as methylamine, (C 1~4 alkyl)2amines, such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C 1~4 Alkoxy-C 2~4 Alkylamines, such as 2-methoxyethylamine, phenyl-C 1~4Alkylamines, such as benzylamine, and amides formed with amino acids, such as glycine or its esters.

[0095] A pharma- ceutically acceptable prodrug of a compound of formula (I) having an amino group is suitably, for example, an in vivo cleavable amide derivative thereof. Pharmaceutically acceptable amides derived from an amino group suitably include, for example, 1~10 Alkanoyl groups include, for example, acetyl, benzoyl, phenylacetyl, and substituted benzoyl and amides formed with phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 Alkyl)piperazin-1-ylmethyl.

[0096] The in vivo effects of the compounds of formula (I) may be exerted in part by one or more metabolic products formed in the human or animal body following administration of the compounds of formula (I).As described below, the in vivo effects of the compounds of formula (I) may also be exerted as a result of the metabolism of a precursor compound (prodrug).

[0097] Although the present invention may relate to compounds or particular groups of compounds defined herein with any optional, preferred or suitable feature or with an otherwise specific embodiment, the present invention may also relate to compounds or particular groups of compounds that specifically do not have said optional, preferred or suitable features or specific embodiments.

[0098] The present invention suitably excludes any individual compound that does not have biological activity as defined herein.

[0099] [Synthesis] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular methods for the preparation of these compounds are further described in the accompanying examples.

[0100] In the descriptions of synthetic methods provided herein, and in any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedures, can be selected by one of ordinary skill in the art.

[0101] It is understood by one skilled in organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0102] It is understood that during the synthesis of the compounds according to the invention in the methods defined herein, or during the synthesis of some of the starting materials, it may be desirable to protect some of the substituents to prevent undesired reactions. The skilled chemist will understand how such protecting groups can be introduced and subsequently removed, when such protection is required.

[0103] For examples of protecting groups, see one of the many general texts on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green, published by John Wiley & Sons, Inc. Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such method being chosen to effect removal of the protecting group with minimal disturbance of other groups in the molecule.

[0104] Thus, if the reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0105] The protecting group for amino or alkylamino group is suitably, for example, an acyl group, for example, an alkanoyl group, such as acetyl, an alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example, benzyloxycarbonyl, or an aroyl group, for example, benzoyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group, for example, an alkanoyl or alkoxycarbonyl group or an aroyl group, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, for example, lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, may be removed by treatment with a suitable acid, for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, may be removed, for example, by hydrogenation over a catalyst, for example palladium on carbon, or by treatment with a Lewis acid, for example boron tris(trifluoroacetate). An alternative protecting group for a primary amino group is, suitably, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0106] The protecting group for the hydroxy group is suitably, for example, an acyl group, for example, an alkanoyl group, such as acetyl, an aroyl group, for example, benzoyl, or an arylmethyl group, for example, benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group, for example, an alkanoyl group, or an aroyl group, can be removed, for example, by hydrolysis with a suitable base, for example, an alkali metal hydroxide, for example, lithium, sodium hydroxide, or ammonia. Alternatively, an arylmethyl group, for example, a benzyl group, can be removed, for example, by hydrogenation over a catalyst, for example, palladium on carbon.

[0107] A protecting group for a carboxy group is suitably, for example, an esterifying group, a methyl or ethyl group which may be removed, for example, by hydrolysis with a base, for example sodium hydroxide, or, for example, a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid, for example trifluoroacetic acid, or a benzyl group which may be removed, for example, by hydrogenation, for example over a catalyst, for example palladium on carbon.

[0108] Resins can also be used as protecting groups.

[0109] The methodology used to synthesize compounds of formula (I) will vary depending on the nature of R1, R2, R3X1, L and Q and any associated substituents thereof. Suitable methods for their preparation are further described in the accompanying examples.

[0110] After the compounds of formula (I) have been synthesised by any one of the processes defined herein, those processes then include the following further steps, namely: (i) removing any protecting groups present; (ii) converting a compound of formula (I) to another compound of formula (I); (iii) forming a pharma- ceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof It may further include:

[0111] An example of (ii) above is where a compound of formula (I) is synthesised and then one or more of the groups R1, R2, R3X1, L and Q can be further reacted to change the nature of that group to provide an alternative compound of formula (I). For example, the compound can be reacted to convert R3 to a substituent other than hydrogen.

[0112] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0113] [Biological activity] The pharmacological effects of the compounds of this invention can be determined using the assays described in the accompanying Biological Examples section. [Brief description of the drawings]

[0114] [Figure 1] Figure 1 shows Western blot data demonstrating ERK5 levels in MDA-MB-468 at different concentrations of OS1. The graph shows quantification of protein levels relative to β-actin. The graph on the left shows ERK5 levels, and the graph on the right shows BRD4 levels at different concentrations of OS1. [Diagram 2] FIG. 13 shows ERK5 Western blot and schematic quantification of ERK5 levels relative to β-actin in MDA_MB-468 at different concentrations of CE207, OS3 and OS4. [Diagram 3] FIG. 13 shows ERK5 Western blot and schematic quantification of ERK5 levels relative to β-actin in MDA-MB-468 at different concentrations of OS6 and OS7. [Figure 4] FIG. 13 shows ERK5 Western blot and schematic quantification of ERK5 levels relative to β-actin in MDA-MB-468 at different concentrations of OS9, OS10 and OS11. [Diagram 5] FIG. 13 shows ERK5 Western blot and schematic quantification of ERK5 levels relative to β-actin in MDA_MB-468 at different concentrations of OS12, OS13 and OS14. [Figure 6] Western blot of BRD4, ERK5 and β-actin in triple-negative breast cancer cell line MDA-MB-468 in response to different concentrations of OS17. The graph on the right shows a schematic representation of relative protein levels of ERK5 normalized to β-actin. [Figure 7] FIG. 1 shows the relative protein levels of ERK5 to β-actin at different concentrations of OS11, OS13 and OS17. [Figure 8]Western blot of ERK5, phosphorylated forms of ERK5, upstream activators of ERK5, MEK5, as well as BRD4, ERK1 / 2 and β-actin in three triple-negative breast cancer cell lines: MDA-MB-231, MDA-MB-468 and SUM159 in response to different concentrations of OS1. The graph on the right shows the relative protein levels normalized to β-actin. [Figure 9] Western blots of ERK5, BRD4, MEK5 and β-actin in three triple-negative breast cancer cell lines: MDA-MB-231, MDA-MB-468 and SUM159 in response to 1 μM OS1 or 2.5 μM AX15836 (ERK5 kinase inhibitor 5,11-dihydro-2-[[2-ethoxy-4-[[4-(4-methyl-1-piperazinyl)-1-piperidinyl]carbonyl]phenyl]amino]-5-methyl,11-(methylsulfonyl)-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one) and the effect of a single dose of OS1 and repeated addition of OS1 every 48 hours for up to two weeks over a period of time. The ERK5 kinase inhibitor AX15836 is used as a comparison. [Figure 10] Immunofluorescence images of the effect of 1 μM OS1 or 2.5 μM AX15836 on ERK5 levels and morphology in three triple-negative breast cancer cell lines: MDA-MB-231, MDA-MB-468, and SUM159. [Figure 11] Figure 1 shows the relative mRNA levels of EMT, angiogenesis and inflammation regulators in response to 0.1 or 1 μM OS1 treatment for 24 hours in three triple-negative breast cancer cell lines: MDA-MB-231, MDA-MB-468 and SUM159. Results are normalized to internal loading controls PGK1 or ACTB. [Figure 12] A figure showing a comparison of OS1 with Example 7 of WO 2021 / 061894. [Figure 13] A figure showing a comparison of OS11 with Example 7 of WO 2021 / 061894. [Figure 14A-B]Figure 14A shows effective knockdown of ERK5 by OS11 in tumor compartments and PBMCs in vivo, and Figure 14B shows that OS11 has an anti-tumor effect equal to that of PD1-inhibition, and that combined treatment of OS11 with PD1 inhibition has no additional effect beyond either agent alone.

[0115] The pharmacological properties of the compounds of formula (I) vary with structural variations, but, as expected, the compounds of the invention are found to be active in these assays.

[0116] [Pharmaceutical composition] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the invention as defined above, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in association with a pharma- ceutically acceptable diluent or carrier.

[0117] The compositions of the present invention may be in a form suitable for oral use (e.g. as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g. as a finely divided powder or liquid aerosol), administration by insufflation (e.g. as a finely divided powder) or parenteral administration (e.g. as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0118] The compositions according to the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0119] An effective amount of a compound according to the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0120] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain from 0.5 mg to 0.5 g (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg) of active agent, combined with an appropriate and convenient amount of excipient, which may vary, for example, from about 5 to about 98 weight percent of the total composition.

[0121] The size of an dose of a compound of formula (I) administered for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, in accordance with well known principles of medicine.

[0122] In using the compounds according to the invention for therapeutic or prophylactic purposes, this is generally carried out so that a daily dose in the range, for example 0.1 mg / kg to 75 mg per kg of body weight is administered, taking into account the cases where divided doses are required. Generally, lower doses are administered when parenteral routes are used. Thus, for example, in the case of intravenous or intraperitoneal administration, a dose in the range, for example 0.1 mg to 30 mg per kg of body weight, is generally used. Similarly, in the case of administration by inhalation, a dose in the range, for example 0.05 mg to 25 mg per kg of body weight, is used. Oral administration may also be suitable, particularly in the form of tablets. Usually, a unit dosage form contains about 0.5 mg to 0.5 g of the compounds according to the invention.

[0123] Therapeutic Uses and Applications The present invention provides compounds that function as degraders of ERK5.

[0124] The present invention provides a method for reducing ERK5 enzyme activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0125] The present invention also provides a method of treating a disease or disorder associated with ERK5 activity in a patient in need of such treatment, comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

[0126] The present invention provides a method of inhibiting cell proliferation in vitro or in vivo, comprising the step of contacting a cell with an effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0127] The present invention relates to a method for treating cancer, such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, such as Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigment epithelium, and retinal pigment epithelium. degeneration, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic injury associated myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0128] The present invention provides a method for treating a patient in need of such treatment, comprising: a) fibrotic diseases, e.g., wound healing disorders, pulmonary fibrosis, b) Inflammatory diseases, e.g., psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) Pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia The present invention provides a method for treating a patient suffering from rheumatoid arthritis, comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0129] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

[0130] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising the step of administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, suitably selected from triple-negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer or squamous cell carcinoma.

[0131] The present invention provides a method of treating a central nervous system (CNS) disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, suitably the CNS disorder being Parkinson's disease or dementia.

[0132] The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0133] The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of a proliferative condition.

[0134] The present invention relates to a method for treating cancer, such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, such as Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplasia. In one embodiment, the present invention provides a compound as defined herein, or a pharmacologic acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of chronic inflammatory bowel syndrome, ischemic injury associated myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood disorders such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0135] The present invention relates to: a) fibrotic diseases, e.g., wound healing disorders, pulmonary fibrosis, b) Inflammatory diseases, e.g., psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) Pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of

[0136] The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer. In a particular embodiment, the cancer is selected from triple-negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, or squamous cell carcinoma.

[0137] The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a central nervous system (CNS) disorder. In a particular embodiment, the central nervous system (CNS) disorder is Parkinson's disease or dementia.

[0138] The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, for use in reducing ERK5 enzymatic activity.

[0139] The present invention provides a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder associated with ERK5 activity.

[0140] Diseases or disorders in which ERK5 is associated include cancer, e.g., triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, e.g., systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, e.g., cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, e.g., Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, muscle atrophy, and osteoporosis. myelodysplastic syndromes, ischemic injury-related myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0141] The invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative condition.

[0142] The present invention relates to a method for treating cancer, such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; cardiovascular diseases, such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, such as Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; bone The present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of myelodysplastic syndromes, ischemic injury-related myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0143] The present invention relates to: a) fibrotic diseases, e.g., wound healing disorders, pulmonary fibrosis, b) Inflammatory diseases, e.g., psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) Pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia The present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of

[0144] The present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of a human cancer. More suitably, the cancer is selected from triple-negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer or squamous cell carcinoma.

[0145] The invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a central nervous system (CNS) disorder, suitably for use in the treatment of Parkinson's disease or dementia.

[0146] The present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the reduction of ERK5 enzymatic activity.

[0147] The invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with ERK5 activity.

[0148] "Proliferative disorder" is used interchangeably herein and refers to unwanted or uncontrolled cell proliferation, either in vitro or in vivo, of excessive or abnormal cells, e.g., neoplastic or hyperplastic proliferation. Proliferative conditions include, for example, premalignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0149] The anti-proliferative effects of the compounds with which the invention is concerned have particular use in the treatment of human cancers (by virtue of their reduction in ERK5 enzyme activity through degradation of the ERK5 enzyme).

[0150] Anti-cancer effects may occur through one or more mechanisms, including, but not limited to, modulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of a tumor from its origin), inhibiting invasion (the spread of tumor cells into adjacent normal structures), or promoting apoptosis (programmed cell death).

[0151] In one particular embodiment of the invention, the proliferative condition to be treated is cancer, hi one particular embodiment, the cancer is selected from triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer or squamous cell carcinoma.

[0152] In one particular embodiment of the invention, the fibrotic disease to be treated is a wound healing disorder or pulmonary fibrosis.

[0153] In one particular embodiment of the invention, the inflammatory disease to be treated is psoriasis or asthma.

[0154] In one particular embodiment of the invention, the central nervous system (CNS) disorder to be treated is Parkinson's disease or dementia.

[0155] In one particular embodiment of the invention, the disease or disorder to be treated is cancer, such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer and squamous cell carcinoma; inflammatory diseases, such as systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reaction, asthma, COPD, rhinitis and upper respiratory tract diseases; cardiovascular diseases, such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, such as Alzheimer's disease, dementia, AIDS-related dementia, Parkinson's disease, and the like. glomerulonephritis; myelodysplastic syndromes, ischemic injury associated myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, diabetes, pain, fibrotic diseases such as wound healing disorders and pulmonary fibrosis; and cancer pain.

[0156] [Administration route] The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, either systemically / peripherally or locally (ie, at the desired site of action).

[0157] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., patches, plasters, etc.); transmucosally (including, e.g., patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via aerosol, e.g., through the mouth or nose, using); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intraarticular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; parenterally, e.g., subcutaneously or intramuscularly, by placement of a depot or reservoir.

[0158] [Combination therapy] The antiproliferative treatment as defined above may be applied as a monotherapy or may involve, in addition to the compound according to the invention, conventional surgery or radiation therapy or chemotherapy, which may include one or more of the following categories of antiproliferative agents: (i) As used in medical oncology, other antiproliferative / antineoplastic agents and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor anticancer agents. bioagents (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors such as epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin; (ii) Cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (such as anastrozole, letrozole, borazole and exemestane) and inhibitors of 5α-reductase, such as finasteride; (iii) anti-invasion agents [e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and c-Src kinase family inhibitors such as bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, inhibitors of urokinase-type plasminogen activator receptor function, or antibodies against heparanase]; (iv) inhibitors of growth factor function, for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any of the growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include 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)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6 ,7-Bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors, e.g., lapatinib, etc.; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, For example, imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example, Ras / Raf signaling inhibitors, for example, farnesyltransferase inhibitors, for example, sorafenib (BAY43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, ab l kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors; (v) Antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor, [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindole-5- (yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 of WO 00 / 47212), compounds such as those disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354, as well as compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin αvβ3 function and angiostatin)]; (vi) vascular damaging agents, such as combretastatin A4 and the compounds disclosed in WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; (viii) antisense therapy, e.g., directed to the targets set forth above, e.g., ISIS2503, anti-ras antisense, etc.; (ix) gene therapy approaches, including, for example, approaches that replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those that use cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches that increase a patient's resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and (x) Immunotherapeutic approaches, including ex-vivo and in-vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, approaches to reduce T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

[0159] In one particular embodiment, the above defined antiproliferative treatment may involve, in addition to the compounds according to the invention, conventional surgery or radiation therapy or chemotherapy.

[0160] Such conjoint treatment may be accomplished by the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage ranges set forth above, and the other pharmacologic-active agent(s) within their approved dosage ranges.

[0161] According to this aspect of the invention there is provided a combination comprising a compound according to the invention as defined above, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent for use in the treatment of cancer (e.g. a cancer involving a solid tumour).

[0162] According to this aspect of the invention there is provided a combination comprising a compound according to the invention as defined above, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents described herein above, for use in the treatment of a proliferative condition, such as cancer (e.g. a cancer involving a solid tumour).

[0163] In a further aspect of the invention there is provided a compound according to the invention or a pharma- ceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer, optionally in combination with another anti-tumour agent selected from those described herein above.

[0164] "Combination" is understood herein to mean simultaneous, separate or sequential administration. In one aspect of the invention, "combination" means simultaneous administration. In another aspect of the invention, "combination" means separate administration. In a further aspect of the invention, "combination" means sequential administration. If administration is sequential or separate, the delay in administering the second component should not, for example, result in the loss of the beneficial effect of the combination.

[0165] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the present invention, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from those described herein above), in association with a pharma- ceutically acceptable diluent or carrier. EXAMPLES

[0166] [Chemical synthesis] <4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione> [ka]

[0167] 3-Bromophthalic anhydride (840 mg and 3.70 mmol), 3-aminopiperidine-2,6-dione hydrochloride (667 mg and 4.07 mmol) and sodium acetate (364 mg and 4.44 mmol) were suspended in (glacial) acetic acid (30 mL) and heated at 140° C. overnight. The reaction was cooled to 25° C., concentrated in vacuo and water (30 mL) was added to the crude. The solid was filtered off to give 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (730 mg, 59%) as an off-white solid. 1 mp:>300℃. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.3 Hz, 1H), 7.79 (apparently t, J = 7.7 Hz, 1H), 5.18 (dd, J = 12.8, 5.4 Hz, 1H), 2.95-2.86 (m, 1H,), 2.66 - 2.57 (m, 2H), 2.11-2.05 (m, 1H). m / z (ES + ) = 336.7.

[0168] <((pent-4-yn-1-yloxy)methyl)benzene> [ka]

[0169] NaH (1.9 g, 47.6 mmol) was suspended in THF (95 mL) and 4-pentynol (2.0 g, 23.8 mmol) was added dropwise at 0° C. Then benzyl bromide (2.6 mL, 21.9 mmol) was added dropwise and allowed to stir overnight. Saturated aqueous ammonium chloride solution (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL), the organics were dried over MgSO4 and concentrated in vacuo. The crude was purified by flash column chromatography (20:1, hexane:EtOAc) and the clean fractions were concentrated in vacuo to give ((pent-4-yn-1-yloxy)methyl)benzene (2.0 g, 52%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.32 - 7.07 (m, 5H), 4.42 (s, 2H), 3.49 (t, J = 6.2 Hz, 2H), 2.23 (td, J = 7.1, 2.6 Hz, 2H), 1.85 (t, J = 2.6 Hz, 1H), 1.78 - 1.69 (m, 2H).

[0170] <4-(5-(benzyloxy)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione> [ka]

[0171] 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1000 mg and 2.97 mmol), pent-4-yn-1-yloxy)methyl)benzene (1030 mg and 5.95 mmol), copper iodide (66 mg and 0.35 mmol) and Pd(PPh3)2Cl2 (126 mg and 0.18 mmol) were suspended in DMF (10 mL). The reaction was purged with argon three times and evacuated, then NEt3 (10 mL) was added, purged three more times, evacuated and heated to 60 °C overnight. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL), dried over MgSO4 and concentrated. The crude material was purified by flash column chromatography (3:1, hexanes:EtOAc) and the clean fractions were taken and concentrated in vacuo to give 4-(5-(benzyloxy)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (850 mg, 66%) as a brown solid. 1 H NMR (400 MHz, chloroform-d) δ 8.01 (br.s, 1H), 7.71 (m, 1H), 7.62 - 7.52 (m, 1H), 7.31 - 7.20 (m, 5H), 4.90 (dd, J = 12.3, 5.3 Hz, 1H), 4.48 m / z (ES) + ) = 431.3.

[0172] <2-(2,6-dioxopiperidin-3-yl)-4-(5-hydroxypentyl)isoindoline-1,3-dione> [ka]

[0173] 4-(5-(benzyloxy)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (126 mg, 0.21 mmol) was suspended in EtOH (10 mL). Palladium on carbon (10% w / w, 20 mg and 0.023 mmol) was added under argon, followed by a hydrogen balloon and stirring at 25 °C overnight. The reaction was diluted with EtOH (40 mL), filtered through Celite, and the filtrate was concentrated in vacuo to give 2-(2,6-dioxopiperidin-3-yl)-4-(5-hydroxypentyl)isoindoline-1,3-dione (50 mg, 49%) as a white solid. mp: 176-178 °C. 1 H NMR (400 MHz, methanol-d4) δ 7.67 - 7.50 (m, 3H), 5.03 (dd, J = 12.5, 5.5 Hz, 1H), 3.45 (t, J = 6.6 Hz, 2H), 3.05 - 2.98 (m, 2H), 2.84 - 2.57 (m, 3H), 2.10 - 1.98 (m, 1H), 1.91 (s, 1H), 1.67 - 1.53 (m, 2H), 1.52 - 1.44 (m, 2H), 1.41 - 1.33 (m, 2H). m / z (ES + ) = 345.1.

[0174] <5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanal> [ka]

[0175] 2-(2,6-dioxopiperidin-3-yl)-4-(5-hydroxypentyl)isoindoline-1,3-dione (623 mg, 1.80 mmol) was suspended in DCM (20 mL) and pyridinium chlorochromate (582 mg, 2.70 mmol) was added in one portion and allowed to stir at 25° C. for 3 h. Fluorosil was then added to the reaction mixture and allowed to stir for a further 1 h before filtering through a pad of Celite, washing the Celite pad with DCM (50 mL) and concentrating the organics to leave 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanal as a grey solid. m / z (ES + ) = 343.3

[0176] <tert-ブチル4-(4-(5-(2-(2,6-ジオキソピペリジン-3-イル)-1,3-ジオキソイソインドリン-4-イル)ペンチル)ピペラジン-1-イル)ピペリジン-1-カルボキシレート> [ka]

[0177] 1-(1-Boc-piperdin-4-yl)-piperazine (39 mg, 0.13 mmol) was suspended in anhydrous DCM (10 mL) over 4 Å molecular sieves and stirred for 10 min. 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanal (42 mg, 0.13 mmol) was added and stirred for 3 h. Sodium triacetoxyborohydride (82 mg, 0.39 mmol) was added and stirred at 25° C. for 3 h. Water (20 mL) was added and extracted with DCM (2×30 mL). The organics were dried over MgSO4 and concentrated in vacuo to give tert-butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentyl)piperazin-1-yl)piperidine-1-carboxylate (40 mg, 54% (2 steps)) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.65 (d, J = 7.5 Hz, 1H), 7.56 (apparent t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 4.94 - 4.85 (m, 1H), 4.13 - 3.99 (m, 2H), 3.00 (td. (ES + ) = 596.0.

[0178] <4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentyl)piperazin-1-yl)piperidine-1-ium hydrochloride> [ka]

[0179] tert-Butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentyl)piperazin-1-yl)piperidine-1-carboxylate (40 mg, 0.067 mmol) was suspended in THF (5 mL). HCl in dioxane (4N, 3 mL) was added and stirred at 25° C. overnight. The reaction was concentrated under reduced pressure to leave 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentyl)piperazin-1-yl)piperidin-1-ium hydrochloride (32 mg, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H, NH(imide)), 7.84 - 7.65 (m, 3H), 5.15 (dd, J = 13.2, 6.4 Hz, 1H), 3.64 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.16 - 3.00 (m, 4H), 2.99 - 2.78 (m, 4H), 2.68 - 2.53 (m, 2H), 2.40 - 1.83 (m, 7), 1.82 - 1.69 (m, 4H), 1.63 (h, J = 6.8, 5.8 Hz, 2H), 1.56 - 1.46 (m, 2H). Two aliphatic protons are hidden by the DMSO peak. m / z (ES + ) = 495.9.

[0180] <5-(methylamino)pyrimidine-2,4-(1H,3H)-dione> [ka]

[0181] 5-Bromouracil (19.10 g, 100.00 mmol) was suspended in 40% aqueous methylamine (160 mL) and heated overnight at 80° C. The reaction was cooled to RT and acidified with 3 M aqueous HCl to form a white precipitate which was filtered and washed with water to give 5-(methylamino)pyrimidine-2,4(1H,3H)-dione (9.3 g, 66%) as a white solid. 2 mp:199~202℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.14 (s, 1H), 6.19 (d, J = 5.0 Hz, 1H), 4.46 (q, J = 5.5 Hz, 1H) (Me peak hidden by DMSO peak). m / z (ES + ) = 141.1.

[0182] <N-(2,4-ジオキソ-1,2,3,4-テトラヒドロピリミジン-5-イル)-N-メチル-2-ニトロベンズアミド> [ka]

[0183] 5-(Methylamino)pyrimidine-2,4(1H,3H)-dione (2.00 g, 14.80 mmol) was suspended in THF (10 mL), cooled to 0° C., and aqueous NaOH (2M, 20 mL) was added, followed by dropwise addition of 2-nitrobenzoyl chloride (2.30 mL, 17.8 mmol). The addition reaction was then warmed to 25° C. and stirred for 48 hours. The reaction was acidified to pH 4 with 4M aqueous HCl and allowed to stand for up to 48 hours. The solid was filtered and washed with water to give N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-N-methyl-2-nitrobenzamide (2.60 g, 61%) as a white solid. 2 mp: 259~261℃(decomposed). 1 H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 10.88 (d, J = 3.8 Hz, 1H), 8.10 (dd, J = 8.2, 1.2 Hz, 1H), 7.75 (td, J = 7.5, 1.2 Hz, 1H), 7.64 (ddd, J = 8.2, 7.5, 1.2 Hz, 1H), 7.43 - 7.33 (m, 2H), 3.15 (s, 3H)

[0184] <N-(2,4-ジクロロピリミジン-5-イル)-N-メチル-2-ニトロベンズアミド> [ka]

[0185] N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-N-methyl-2-nitrobenzamide (9.00 g, 27.6 mmol) was suspended in phosphorus oxychloride (50 mL) and N,N-dimethylaniline (2.5 mL). The reaction was heated to 100° C. for 18 h and then cooled to 25° C. It was concentrated in vacuo and the crude was taken directly into the next step (reduction and cyclization). 2

[0186] <2-Chloro-5-methyl-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one> [ka]

[0187] Crude N-(2,4-dichloropyrimidin-5-yl)-N-methyl-2-nitrobenzamide (assumed to be 27.6 mmol) was suspended in acetic acid (100 mL), Fe powder (9.1 g) was added and heated to 60° C. for 4 h. The reaction was cooled to 25° C., the acetic acid was removed in vacuo and the crude was solubilized in DCM / MeOH (50 mL / 20 mL), filtered through Celite and concentrated to leave a white solid. Cold EtOH was added and the solid was collected by filtration to give 2-chloro-5-methyl-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one (5.8 g, 82% (2 steps)) as a white solid. 2 mp:196~201℃. 1 H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 7.98 (dd, J = 8.2, 1.6 Hz, 1H), 7.45 - 7.33 (m, 1H), 7.13 (ddd, J = 8.2, 7.3, 1.0 Hz, 1H), 6.81 (dd, J = 8.2, 1.0 Hz, 1H), 6.66 (s, 1H), 3.51 (s, 3H). m / z= 261.2 ( 35 Cl), 263.2 ( 37 Cl).

[0188] 2-Chloro-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one [ka]

[0189] 2-Chloro-5-methyl-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one (200 mg, 0.77 mmol) was suspended in THF (10 mL). Sodium hydride (60% suspension in mineral oil 61 mg, 1.53 mmol) was added at 0° C. and stirred for 1 h. Methanesulfonyl chloride (0.13 mL and 1.53 mmol) was added dropwise and stirred for 1 h. The reaction was quenched with water (10 mL), extracted with EtOAc (3×20 mL), and the organics were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (1:1, hexanes:EtOAc) and the clean fractions were taken and concentrated in vacuo to give 2-chloro-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one (151 mg, 61%) as a white solid. 2 mp:101~104℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.87 - 7.79 (m, 1H), 7.72 - 7.67 (m, 2H), 7.54 (ddd, J = 8.2, 5.9, 2.5 Hz, 1H), 3.78 (s, 3H), 3.56 (s, 3H). m / z (ES + ) = 339.2 ( 35 Cl), 341.2 ( 37 Cl).

[0190] <Ethyl 3-ethoxy-4-nitrobenzoate> [ka]

[0191] 3-Hydroxy-4-nitrobenzonic acid (1.00 g, 5.46 mmol), potassium carbonate (3.00 g, 16.45 mmol) were suspended in DMF (20 mL). Iodoethane (1.3 mL, 21.74 mmol) was added dropwise and stirred at 25° C. for 18 h. Water (50 mL) was added to the reaction mixture, extracted with EtOAc (3×50 mL), the organics were washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to leave ethyl 3-ethoxy-4-nitrobenzoate (1.01 g, 83%) as an orange oil. 21 H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8.3 Hz, 1H), 7.75 (apparently s, 1H), 7.69 (dd, J = 8.3, 1.5 Hz, 1H), 4.48 - 4.39 (q, J = 6.9 Hz, 2H), 4.31 - 4.23 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 6.9 Hz, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0192] <Ethyl 4-amino-3-ethoxybenzoate> [ka]

[0193] Ethyl 3-ethoxy-4-nitrobenzoate (570 mg 2.39 mmol) was suspended in EtOH (10 mL) and THF (10 mL). Palladium on carbon (10% w / w, 20 mg, 0.23 mmol) was added under argon, then the reaction mix was placed in a hydrogen atmosphere and stirred for 18 hours. The reaction was diluted with EtOH (20 mL), filtered through Celite, and concentrated in vacuo to give ethyl 4-amino-3-ethoxybenzoate (500 mg, 100%) as a brown solid. 2 mp:86~88℃. 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.60 (dd, J = 8.3, 1.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H). m / z (ES + ) = 210.0.

[0194] <Ethyl 3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoate> [ka]

[0195] 2-Chloro-5-methyl-11-(methylsulfonyl)-5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one (270 mg, 1.04 mmol), ethyl 4-amino-3-ethoxybenzoate (261 mg, 1.25 mmol), K2CO3 (828 mg, 6.00 mmol) and t BuXPhos Gen 3 precatalyst (65 mg, 0.08 mmol) t Suspended in BuOH (15 mL), evacuated and purged with argon three times, then heated at 100° C. for 18 h. Added water (50 mL), extracted with EtOAc (3×30 mL), dried over MgSO4, and concentrated in vacuo. The crude was purified by flash column chromatography (10:1, toluene:EtOAc) and the clean fractions were taken and concentrated under reduced pressure to give ethyl 3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoate (110 mg, 23%) as an orange oil.1 H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 1.5 Hz, 1H), 8.46 (dd, J = 8.5, 1.4 Hz, 1H), 8.01 (s, 1H), 7.94 (dt, J = 7.8, 1.6 Hz, 1H), 7.73 (dt, J = 8.5, 1.7 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.53 - 7.43 (m, 2H), 4.37 (q, J = 7.0 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.62 (s, 3H), 3.49 (s, 3H, N-Me), 1.51 (t, J = 7.0 Hz, 3H), 1.40 (t, J = 7.2, 3H). m / z= 511.1.

[0196] <3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoic acid> [ka]

[0197] 3-Ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoic acid (40 mg, 0.08 mmol) and LiOH (10 mg, 0.43 mmol) were suspended in THF (5 mL), HO (1 mL) and MeOH (1 mL) and stirred at 25 °C for 19 h. The reaction was concentrated under reduced pressure and the crude was dissolved in DCM (50 mL) and washed with 1 M aqueous hydrochloric acid (2 x 30 mL). The organics were dried over MgSO4 and concentrated in vacuo to give 3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoic acid (30 mg, 77%) as a white solid. mp: 265-266 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.98 (s, 1H), 8.79 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.78 (dd, J = 7.9, 1.5 Hz, 1H), 7.68 - 7.56 (m, 2H) 7.59 (dd, J = 8.3, 4.0 Hz, 1H), 7.54 - 7.44 (m, 2H), 4.16 (apparently qt, J = 7.0 Hz, 2H), 3.78 (s, 3H, N-Me), 3.50 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). m / z (ES + ) = 484.3.

[0198] [Method A] The alkyne alcohol (1 equiv.), TsCl (1.2 equiv.), catalytic DMAP and NEt3 (3 equiv.) were solubilized in DCM (0.1 mM) and stirred at 25° C. for 17 h. Saturated aqueous NaHCO3 (20 mL) was added and the crude was extracted with DCM (2×20 mL), the organics were combined, dried over MgSO4, filtered and concentrated in vacuo. The crude material was taken on to the next step without further purification.

[0199] <But-3-yn-1-yl 4-methylbenzenesulfonate> [ka]

[0200] Synthesized using Method A. 553mg, 44%. 1 H NMR (500 MHz, chloroform-d) δ 7.83 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.13 (t, J = 7.0 Hz, 2H), 2.58 (td, J = 7.0, 2.7 Hz, 2H), 2.48 (s, 3H), 1.99 (t, J = 2.7 Hz, 1H).

[0201] <ペンタ-4-イン-1-イル4-メチルベンゼンスルホネート>

change

[0202] Method A uses して to synthesize した. 600mg, 57% 1 H NMR (400 MHz, クロロホルム-d) δ 7.79 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 2.45 (s, 3H), 2.16 (td, J = 7.0, 2.7 Hz, 2H), 1.92 (t, J = 2.7 Hz, 1H), 1.82 - 1.72 (m, 2H), 1.61 - 1.51 (m, 2H).

[0203] <ヘキサ-5-イン-1-イル4-メチルベンゼンスルホネート>

change

[0204] Method A uses して to synthesize した. 1.01g, 62% 1 H NMR (500 MHz, クロロホルム-d) δ 7.75 - 7.68 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 3.96 (t, J = 6.5 Hz, 2H), 2.38 (s, 3H), 2.08 (td, J = 6.8, 2.7 Hz, 2H), 1.86 (t, J = 2.7 Hz, 1H), 1.64 - 1.54 (m, 2H), 1.46 - 1.29 (m, 4H).

[0205] <ヘプタ-6-イン-1-イル4-メチルベンゼンスルホネート>

change

[0206] Synthesized using Method A. Material taken directly into next step.

[0207] <Oct-7-yn-1-yl 4-methylbenzenesulfonate> [ka]

[0208] Synthesized using Method A. Material taken directly into next step.

[0209] <Nona-8-yn-1-yl 4-methylbenzenesulfonate> [ka]

[0210] Synthesized using Method A. 2.5g, 65% 1 H NMR (500 MHz, chloroform-d) δ 7.72 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 3.95 (t, J = 6.5 Hz, 2H), 2.38 (s, 3H), 2.09 (td, J = 7.1, 2.7 Hz, 2H), 1.86 (t, J = 2.6 Hz, 1H), 1.63 - 1.53 (m, 2H), 1.44 - 1.38 (m, 2H), 1.33 - 1.13 (m, 6H).

[0211] <Deca-9-yn-1-yl 4-methylbenzenesulfonate> [ka]

[0212] Synthesized using Method A. 500mg, 61%. 1H NMR (400 MHz, chloroform-d) δ 7.84 - 7.74 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.01 (t, J = 6.5 Hz, 2H), 2.43 (d, J = 14.4 Hz, 3H), 2.16 (td, J = 7.1, 2.6 Hz, 2H), 1.93 (t, J = 2.7 Hz, 1H), 1.63 (d, J = 14.3 Hz, 4H), 1.50 (dq, J = 14.6, 6.9 Hz, 2H), 1.43 - 1.19 (m, 11H).

[0213] <Methyl 3-iodo-2-methylbenzoate> [ka]

[0214] 3-Iodo-2-methylbenzonic acid (1.00 g, 3.81 mmol) was suspended in MeOH (40 mL). SOCl2 (0.28 mL, 3.81 mmol) was added dropwise at 0 °C and heated to 80 °C for 2 h. The reaction mix was concentrated in vacuo. The residue was quenched with saturated aqueous NaHCO3 (40 mL), extracted with EtOAc (3 x 20 mL), and the organics were dried over MgSO4, filtered, and concentrated to leave methyl 3-iodo-2-methylbenzoate (0.85 g, 80%). 1 H NMR (500 MHz, chloroform-d) δ 7.98 (dd, J = 7.8, 1.3 Hz, 1H), 7.73 (dd, J = 7.8, 1.3 Hz, 1H), 6.92 (apparent t, J = 7.8 Hz, 1H), 3.90 (s, 3H), 2.66 (s, 3H).

[0215] <3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione> [ka]

[0216] Methyl 3-iodo-2-methylbenzoate (850 mg, 3.07 mmol) was suspended in diethyl carbonate (8 mL) and NBS (653 mg, 3.69 mmol) and AIBN (101 mg, 0.616 mmol) were added in one portion and stirred at 80° C. for 17 h. The reaction mix was concentrated in vacuo, then suspended in MeCN (10 mL) and 3-aminopiperidone hydrochloride (595 mg, 3.64 mmol) and NEt3 (0.66 mL, 4.66 mmol) were added and heated at 80° C. for 17 h. The reaction mix was cooled, concentrated in vacuo, water (25 mL) was added and the resulting solid was filtered to leave 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a purple solid. 1 H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.37 (apparently t, J = 7.6 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 - 4.10 (m, 2H), 2.98- 2.88 (m, 1H), 2.68 - 2.44 (m, 3H), 2.10 - 1.99 (m, 1H).

[0217] [Method B] The alkyne tosylate (1 equiv.), 4-piperzin-1-yl-piperidine-1-carbooxylic acid tert-butyl ester (2 equiv.), Cs2CO3 (3 equiv.) and NaI (catalytic) were solubilized in MeCN (0.1 mM). The reaction mix was heated at 80° C. for 17 h. The reaction mix was concentrated in vacuo and the crude was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (2×20 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude mix was taken on to the next step.

[0218] 3-(4-Iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 eq), alkyne (2 eq), Pd(PPh3)2Cl2 (0.06 eq), CuI (0.03 eq) were solubilized in DMF (0.1 mM), purged with argon, NEt3 (10 eq) was added, and the mixture was heated to 80 °C for 2 h. The reaction was cooled to RT, H2O (20 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The organic layer was dried over celite, purified by acidic reverse phase, clean fractions were collected, and concentrated in vacuo.

[0219] <tert-Butyl 4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS3)>

Chemical formula

[0220] Synthesized using Method B. 61 mg, 10%. m / z (ES + ) = 564.4,

[0221] <tert-Butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)penta-4-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of CE207)>

Chemical formula

[0222] Synthesized using Method B. 46 mg, 64%. m / z (ES + ) = 578.1

[0223] <tert-Butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS4)> [Chemical Formula] Synthesized using Method B. 90 mg, 33%. m / z (ES + ) = 592.5

[0224] <tert-Butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS6)> [Chemical Formula]

[0225] Synthesized using Method B. 40 mg, 41% m / z (ES + ) = 626.5

[0226] <tert-Butyl 4-(4-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS9)> [Chemical Formula]

[0227] Synthesized using Method B. 120 mg, 35%. m / z (ES + ) = 638.5

[0228] <tert-Butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-en-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS10)>

Chemical Structure

[0229] Synthesized using Method B. 40 mg, 22%. m / z (ES + ) = 620.4

[0230] <tert-Butyl 4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)nona-8-en-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS11)>

Chemical Structure

[0231] Synthesized using Method B. 121 mg, 36%. m / z (ES + ) = 634.1

[0232] <tert-Butyl 4-(4-(10-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)deca-9-en-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate of OS14)>

Chemical Structure

[0233] Synthesized using Method B. 100 mg, 32%. m / z (ES + ) = 648.4

[0234] [Method C] Phthalic anhydride (1 eq.), 3-aminopiperidine-2,6-dione hydrochloride (1.2 eq.) and sodium acetate (1.2 eq.) were suspended in acetic acid (glacial, 0.1 mmol) and heated at 140° C. overnight. The reaction was cooled to 25° C., concentrated in vacuo, diluted with water (30 mL) and the solids filtered to give the desired products. These products do not ionize well by MS.

[0235] <4-Fluoro-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione> [ka]

[0236] Synthesized by Method C. 800mg, 48%

[0237] <2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione> [ka]

[0238] Synthesized by Method C. 800mg, 48%

[0239] <2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-1,3-dione> [ka]

[0240] 4-Fluoro-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (200 mg, 0.72 mmol), 6-aminohexanol (84 mg, 0.72 mmol) and DIPEA (0.38 mL, 2.1 mmol) were suspended in DMF (5 mL) and heated at 80° C. for 17 h. The reaction was cooled and diluted with HO (30 mL), which was extracted with EtOAc (3×10 mL), the organics combined, dried over MgSO, filtered, concentrated in vacuo and the material purified by acidic reverse phase to leave 2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-1,3-dione (30 mg, 11%) as a brown oil. m / z (ES + ) = 374.3

[0241] <6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl 4-methylbenzenesulfonate> [ka]

[0242] 2-(2,6-Dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-1,3-dione (30 mg, 0.080 mmol), TsCl (17 mg, 0.088 mmol) and NEt3 (0.02 mL, 0.12 mmol) were suspended in DCM (5 mL) and catalytic amount of DMAP was added and allowed to stir at 25° C. for 17 h. The reaction mix was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with DCM (3×10 mL). The organics were combined, dried over MgSO4, filtered and concentrated in vacuo. The material was taken directly into the next step.

[0243] <tert-ブチル4-(4-(6-((2-(2,6-ジオキソピペリジン-3-イル)-1,3-ジオキソイソインドリン-4-イル)アミノ)ヘキシル)ピペラジン-1-イル)ピペリジン-1-カルボキシレート> [ka]

[0244] The material from the previous step was taken up in MeCN (5 mL) and 4-piperzin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.19 mmol), Cs2CO3 (61 mg, 0.19 mmol) and NaI (3 mg, 0.03 mmol) were added and heated to 50° C. for 17 h. The material was then concentrated in vacuo and the crude was taken up in saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (3×10 mL), the organics were combined, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by acidic reverse phase and the clean fractions were taken and concentrated in vacuo to leave tert-butyl 4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)piperidine-1-carboxylate (11 mg, 34%). m / z (ES + ) = 625.2

[0245] <2-(2,6-dioxopiperidin-3-yl)-5-((6-hydroxyhexyl)amino)isoindoline-1,3-dione> [ka]

[0246] 4-Fluoro-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (200 mg, 0.72 mmol), 6-aminohexanol (252 mg, 2.1 mmol) and DIPEA (0.38 mL, 2.1 mmol) were suspended in NMP (5 mL) and heated at 80° C. for 17 h. The reaction was cooled and diluted with HO (30 mL), which was extracted with EtOAc (3×10 mL), the organics were combined, dried over MgSO, filtered, concentrated in vacuo and the material was purified by acidic reverse phase to leave 2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-1,3-dione (60 mg, 22%). m / z (ES +) = 374.3

[0247] <6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl 4-methylbenzenesulfonate> [ka]

[0248] 2-(2,6-Dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-1,3-dione (60 mg, 0.16 mmol), TsCl (36 mg, 0.19 mmol) and NEt3 (0.07 mL, 0.48 mmol) were suspended in DCM (3 mL) and catalytic amount of DMAP was added and allowed to stir at 25° C. for 17 h. The reaction mix was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with DCM (3×10 mL). The organics were combined, dried over MgSO4, filtered and concentrated in vacuo. The material was taken directly into the next step.

[0249] <tert-ブチル4-(4-(6-((2-(2,6-ジオキソピペリジン-3-イル)-1,3-ジオキソイソインドリン-5-イル)アミノ)ヘキシル)ピペラジン-1-イル)ピペリジン-1-カルボキシレート> [ka]

[0250] The material from the previous step was taken up in MeCN (5 mL) and 4-piperzin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.19 mmol), Cs2CO3 (61 mg, 0.19 mmol) and NaI (3 mg, 0.03 mmol) were added and heated to 50° C. for 17 h. The material was then concentrated in vacuo and the crude was taken up in saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (3×10 mL), the organics were combined, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by acidic reverse phase and the clean fractions were taken and concentrated in vacuo to leave tert-butyl 4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)piperidine-1-carboxylate (11 mg, 34%). m / z (ES + ) = 625.3

[0251] <2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione> [ka] Synthesized by Method C. 2.5g, 56%. m / z (ES + ) = 273.1

[0252] <2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)oxy)isoindoline-1,3-dione> [ka]

[0253] 1,6-Hexanediol (212 mg, 2.16 mmol) and triphenylphosphine (561 mg, 2.16 mmol) were suspended in THF (5 mL) and DIAD (0.42 mL, 2.16 mmol) was added dropwise to the solution and allowed to stir at 25° C. for 30 min. 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (500 mg, 1.80 mmol) was added in one portion and allowed to stir at 25° C. for 3 h. The reaction mix was then concentrated in vacuo and water (30 mL) was added to the crude, then extracted with EtOAc (3×20 mL) and the organics were dried over MgSO4, filtered and concentrated in vacuo. The crude was then taken up in EtOH (15 mL) and ZnCl2 (700 mg, 5.49 mmol) was added in one portion and allowed to stir at 25° C. for an additional 17 h. The mixture was then filtered to leave 2-(2,6-dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)oxy)isoindoline-1,3-dione (600 mg, 40%). m / z (ES + ) = 375.3

[0254] <6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl 4-methylbenzenesulfonate> [ka]

[0255] 2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)oxy)isoindoline-1,3-dione (80 mg, 0.21 mmol), TsCl (50 mg, 0.25 mmol), NEt3 (0.09 mL, 0.63 mmol) and catalytic DMAP were suspended in DCM (5 mL) and stirred at 25° C. for 17 h. The reaction was diluted with saturated aqueous sodium bicarbonate (3×10 mL), extracted with EtOAc (3×10 mL), the organics were combined, dried over MgSO4, filtered and concentrated in vacuo to leave 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl 4-methylbenzenesulfonate (75 mg, 68%).

[0256] <tert-ブチル4-(4-(6-((2-(2,6-ジオキソピペリジン-3-イル)-1,3-ジオキソイソインドリン-4-イル)オキシ)ヘキシル)ピペラジン-1-イル)ピペリジン-1-カルボキシレート> [ka]

[0257] 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl 4-methylbenzenesulfonate (75 mg, 0.14 mmol), tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate hydrochloride (86 mg, 0.28 mmol), Cs2CO3 (136 mg, 0.42 mmol) and catalytic NaI were suspended in MeCN (5 mL) and heated to 80 °C for 17 h. The reaction was cooled, concentrated in vacuo, diluted with HO (10 mL) and extracted with EtOAc (3 x 10 mL). The crude was purified by acidic reverse phase and the clean fractions were taken and concentrated in vacuo to leave tert-butyl 4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)piperazin-1-yl)piperidine-1-carboxylate (50 mg, 57%). m / z (ES + ) = 626.4

[0258] <2-(2,6-dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)oxy)isoindoline-1,3-dione> [ka]

[0259] 1,8 octanediol (1.6 g, 10.99 mmol) and triphenylphosphine (1.15 g, 4.36 mmol) were suspended in THF (40 mL) and DIAD (0.8 mL, 4.36 mmol) was added dropwise to the solution and allowed to stir at 25° C. for 30 min. 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1.00 g, 3.66 mmol) was added in one portion and allowed to stir at 25° C. for 3 h. The reaction mix was then concentrated in vacuo and water (30 mL) was added to the crude, which was then extracted with EtOAc (3×20 mL) and the organics were dried over MgSO4, filtered and concentrated in vacuo. The crude material was then taken up in EtOH (30 mL) and ZnCl2 (1.36 g, 10.99 mmol) was added in one portion and allowed to stir at 25 °C for an additional 17 h. The mixture was then filtered to leave 2-(2,6-dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)oxy)isoindoline-1,3-dione (600 mg, 40%). m / z (ES + ) = 403.1

[0260] <4-((8-bromooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione> [ka]

[0261] 2-(2,6-Dioxopiperidin-3-yl)-4-((8-hydroxyoctyl)oxy)isoindoline-1,3-dione (600 mg, 1.48 mmol), carbon tetrabromide (738 mg, 2.23 mmol) and PPh3 (596 mg, 2.29 mmol) were suspended in THF (20 mL) and heated to 50 °C for 17 h. The reaction was concentrated in vacuo, diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude was then taken up in EtOH (30 mL) and ZnCl2 (600 mg, 4.41 mmol) was added in one portion and allowed to stir at 25 °C for an additional 17 h. The mixture was then filtered and the filtrate was concentrated and purified by flash column chromatography (hexanes / EtOAc (1:5)). The clean fractions were collected and concentrated in vacuo to leave 4-((8-bromooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (70 mg, 10%).

[0262] <tert-ブチル4-(4-(8-((2-(2,6-ジオキソピペリジン-3-イル)-1,3-ジオキソイソインドリン-4-イル)オキシ)オクチル)ピペラジン-1-イル)ピペリジン-1-カルボキシレート> [ka]

[0263] 4-((8-Bromooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (70 mg, 0.15 mmol), tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate hydrochloride (45 mg, 0.15 mmol), CsCO (146 mg, 0.45 mmol) and catalytic NaI were suspended in MeCN (5 mL) and heated to 80 °C for 17 h. The reaction mix was cooled, concentrated in vacuo and the crude was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (3×20 mL) to leave tert-butyl 4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)piperazin-1-yl)piperidine-1-carboxylate (70 mg, 71%). m / z (ES + ) = 654.1.

[0264] <tert-ブチル4-(4-(5-(((2S)-1-((4R)-4-ヒドロキシ-2-((4-(4-メチルチアゾール-5-イル)ベンジル)カルバモイル)ピロリジン-1-イル)-3,3-ジメチル-1-オキソブタン-2-イル)アミノ)-5-オキソペンタノイル)ピペラジン-1-イル)ピペリジン-1-カルボキシレート> [ka]

[0265] VHL tocris (20 mg, 0.036 mmol), tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate hydrochloride (12 mg, 0.039 mmol) and HATU (16 mg, 0.043 mmol) were suspended in DMF (1 mL) and DIPEA was added (12.5 μL, 0.072 mmol) and allowed to stir at 25° C. for 1 h. Diluted with EtOAc (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by basic reverse phase chromatography and the clean fractions were taken, combined and concentrated in vacuo to leave a colorless oil (22 mg, 77%). m / z (ES+ ) = 810.5

[0266] [Method D] Ligase binder (1 eq.) was solubilized in DCM and TFA (half the amount of DCM) was slowly added and stirred at 25° C. for 2 h. The reaction mix was concentrated in vacuum. To this crude material was added 3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoic acid (1 eq.), HATU (3 eq.) and DIPEA (5 eq.) and suspended in DMF. The reaction mix was stirred for 17 h. Water (10 mL) was added and extracted with EtOAc (3×10 mL), dried over Celite, purified by acidic reverse phase and clean fractions were combined to leave the desired final compound.

[0267] [Example 1] <2-(2,6-dioxopiperidin-3-yl)-4-(5-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)pentyl)isoindoline-1,3-dione (OS1)> [ka]

[0268] Synthesized using Method D. (7 mg, 23%). mp: 190-192 °C (dec). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 7.85 - 7.67 (m, 5H), 7.66 - 7.59 (m, 2H), 7.47 (ddd, J = 8.2, 6.3, 2.1 Hz, 1H), 7.06 - 7.03 (m, 1H), 6.97 (dd, J = 8.0, 1.7 Hz, 1H), 5.13 (dd, J = 12.7, 5.4 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.73 (s, 3H), 3.48 (s, 3H), 3.04 (t, J = 7.7 Hz, 3H), 2.89 (ddd, J = 16.7, 13.7, 5.3 Hz, 3H), 2.69 - 2.52 (m, 4H), 2.30 (d, J = 5.9 Hz, 2H), 2.11-2.01 (m, 1H), 1.80 (s, 2H), 1.68 - 1.57 (m, 2H), 1.45 - 1.29 (m, 4H), 1.24 (t, J = 6.8 Hz, 3H). Nine aliphatic protons are hidden by water and unknown. m / z (ES + ) = 961.4

[0269] [Example 2] <3-(4-(5-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (CE207)> [ka]

[0270] Synthesized using Method D. 10 mg, 14% m / z (ES + ) = 941.1 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.99 (s, 1H), 8.73 (s, 1H), 7.83 - 7.68 (m, 3H), 7.55 - 7.42 (m, 2H), 7.04 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.50 - 4.27 (m, 3H), 4.16 - 4.03 (m, 2H), 3.74 (s, 3H), 3.18 (d, J = 4.5 Hz, 1H), 2.93 (ddd, J = 17.9, 13.7, 5.5 Hz, 2H), 2.46 - 2.33 (m, 5H), 2.06 - 1.98 (m, 1H), 1.78 - 1.70 (m, 2H), 1.43 - 1.31 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H).

[0271] [Example 3] <3-(4-(4-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS3)> [ka]

[0272] Synthesized using Method D. 24mg, 23%. m / z (ES + ) = 929.3 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.06 (s, 1H), 8.79 (s, 1H), 8.20 (s, 1H), 7.87 - 7.77 (m, 3H), 7.72 - 7.64 (m, 3H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 (ddd, J = 8.2, 5.8, 2.7 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.05 (dd, J = 8.1, 1.7 Hz, 1H), 5.23 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 - 4.32 (m, 2H), 4.22 - 4.09 (m, 2H), 3.80 (s, 3H), 3.55 (s, 3H), 2.73 - 2.59 (m, 2H), 2.53 - 2.41 (m, 1H), 2.13 (s, 2H), 2.13 - 1.95 (m, 3H), 1.56 (d, J = 12.8 Hz, 2H), 1.32 (t, J = 6.9 Hz, 3H).

[0273] [Example 4] <3-(4-(6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS4)> [ka]

[0274] Synthesized using Method D. 7mg, 18%. m / z (ES + ) = 957.3 1H NMR (500 MHz, DMSO-d6) δ11.02 (s, 1H), 9.01 (s, 1H), 8.73 (s, 1H), 7.81 - 7.71 (m, 2H), 7.67 - 7.60 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 - 4.26 (m, 3H), 4.16 - 4.04 (m, 2H), 3.74 (s, 3H), 3.49 (s, 3H), 3.00 - 2.88 (m, 3H), 2.64 - 2.53 (m, 3H), 2.47 - 2.33 (m, 2H), 2.11 - 1.95 (m, 2H), 1.66 - 1.57 (m, 2H), 1.26 (t, J = 6.9 Hz, 3H).

[0275] [Example 5] <3-(4-(7-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS6)> [ka]

[0276] Synthesized using Method D. 4mg, 10%. m / z (ES + ) = 971.4. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 7.91 (dd, J = 27.5, 8.6 Hz, 2H), 7.84 - 7.76 (m, 1H), 7.50 - 7.46 (m, 1H), 7.46 - 7.31 (m, 3H), 7.18 - 7.01 (m, 1H), 5.16 - 5.08 (m, 1H), 4.97 - 4.83 (m, 1H), 4.59 - 4.33 (m, 4H), 4.30 - 4.16 (m, 2H), 3.90 - 3.75 (m, 1H), 3.72 - 3.60 (m, 2H), 3.51 - 3.39 (m, 4H), 2.80 - 2.64 (m, 3H), 2.45 - 2.24 (m, 6H), 2.18 - 1.88 (m, 6H), 1.81 - 1.68 (m, 2H), 1.55 - 1.36 (m, 4H).

[0277] [Example 6] <2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hexyl)amino)isoindoline-1,3-dione (OS7)> [ka]

[0278] Synthesized using Method D. 11 mg, 63% m / z (ES + ) = 990.3 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.00 (s, 1H), 8.73 (s, 1H), 7.80 - 7.55 (m, 6H), 7.51 - 7.44 (m, 1H), 7.13 - 6.94 (m, 4H), 6.54 (t, J = 6.0 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 4.17 - 4.03 (m, 2H), 3.73 (s, 4H), 3.49 (s, 4H), 3.11 - 2.76 (m, 8H), 1.59 (d, J = 7.8 Hz, 4H), 1.44 - 1.28 (m, 9H), 1.26 (t, J = 6.9 Hz, 3H).

[0279] [Example 7] <3-(4-(3-(2-(2-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS9)> [ka]

[0280] Synthesized using Method D. 9mg, 10%. m / z (ES + ) = 1003.3 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 8.19 (s, 1H), 7.74 (dd, J = 16.5, 7.7 Hz, 3H), 7.65 - 7.42 (m, 4H), 7.04 - 6.93 (m, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 - 4.28 (m, 5H), 4.17 - 4.01 (m, 3H), 3.78 - 3.44 (m, 14H), 3.00 - 2.52 (m, 7H), 2.05 - 1.61 (m, 5H), 1.40 - 1.09 (m, 8H).

[0281] [Example 8] <3-(4-(8-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS10)> [ka]

[0282] Synthesized using Method D. 5mg, 8%. m / z (ES + ) = 985.4, 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.02 (s, 1H), 8.73 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.81 - 7.69 (m, 3H), 7.66 - 7.59 (m, 3H), 7.56 - 7.45 (m, 2H), 7.04 (d, J = 1.7 Hz, 1H), 6.98 (dd, J = 8.0, 1.7 Hz, 1H), 5.17 (dd, J = 13.4, 5.1 Hz, 1H), 4.49 - 4.27 (m, 3H), 4.16 - 4.05 (m, 2H), 3.74 (s, 3H), 3.49 (s, 3H), 2.90 (s, 4H), 2.74 (s, 3H), 2.65 - 2.55 (m, 2H), 2.47 - 2.31 (m, 2H), 2.10 - 1.99 (m, 2H), 1.83 (s, 3H), 1.63 - 1.52 (m, 4H), 1.50 - 1.29 (m, 6H), 1.25 (t, J = 6.9 Hz, 3H).

[0283] [Example 9] <3-(4-(9-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)non-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS11)> [ka]

[0284] Synthesized using Method D. 40mg, 60%. m / z (ES + ) = 999.3 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.01 (s, 1H), 8.75 (s, 1H), 7.81 - 7.71 (m, 3H), 7.67 - 7.60 (m, 3H), 7.57 - 7.47 (m, 2H), 7.05 (d, J = 1.7 Hz, 1H), 6.99 (dd, J = 8.1, 1.7 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 - 4.24 (m, 3H), 4.20 - 4.03 (m, 2H), 3.76 (s, 3H), 3.51 (s, 3H), 2.98 - 2.89 (m, 2H), 2.68 - 2.58 (m, 2H), 2.07 - 1.99 (m, 1H), 1.62 - 1.55 (m, 2H), 1.49 - 1.24 (m, 12H).

[0285] [Example 10] <2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hexyl)oxy)isoindoline-1,3-dione (OS12)> [ka]

[0286] Synthesized using method D. 3mg.4% m / z (ES + ) = 990.1 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.88 - 7.71 (m, 1H), 7.68 - 7.55 (m, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.23 - 6.91 (m, 3H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.76 (s, 1H), 3.51 (s, 2H), 3.09 - 2.63 (m, 4H), 2.44 - 1.70 (m, 7H), 1.63 - 1.02 (m, 8H), 0.91 - 0.80 (m, 1H).

[0287] [Example 11] <2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)butoxy)isoindoline-1,3-dione (OS13)> [ka]

[0288] Synthesized using Method D. 7 mg, 11% m / z (ES + ) = 991.3 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.01 (s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 7.86 - 7.72 (m, 2H), 7.62 (d, J = 5.6 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.14 - 6.91 (m, 2H), 5.09 (dd, J = 13.0, 5.4 Hz, 1H), 4.22 (t, J = 5.8 Hz, 1H), 4.15 - 4.04 (m, 2H), 3.74 (s, 2H), 3.49 (d, J = 1.6 Hz, 3H), 3.14 - 2.84 (m, 5H), 2.08 - 1.99 (m, 1H), 1.84 - 1.72 (m, 3H), 1.66 (s, 2H), 1.51 (s, 2H), 1.46 - 1.32 (m, 3H), 1.31 - 1.22 (m, 3H).

[0289] [Example 12] <3-(4-(10-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)dec-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (OS14)> [ka]

[0290] Synthesized using Method D. 12 mg, 15% m / z (ES + ) = 1013.2

[0291] [Example 13] <2-(2,6-dioxopiperidin-3-yl)-4-((8-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)octyl)oxy)isoindoline-1,3-dione (OS17)> [ka]

[0292] Synthesized using Method D. 40mg, 39%. m / z (ES + ) = 1019.2 1 H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.00 (s, 1H), 8.75 (s, 1H), 7.86 - 7.71 (m, 3H), 7.71 - 7.59 (m, 2H), 7.56 - 7.42 (m, 3H), 7.05 (d, J = 1.7 Hz, 1H), 6.99 (dd, J = 8.1, 1.7 Hz, 1H), 5.10 (dd, J = 12.9, 5.5 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 4.12 (dtt, J = 16.6, 9.6, 7.0 Hz, 2H), 3.76 (s, 3H), 3.51 (s, 3H), 3.44 - 3.29 (m, 3H), 2.90 (ddd, J = 16.9, 14.0, 5.5 Hz, 2H), 2.65 - 2.56 (m, 2H), 2.50 - 2.21 (m, 7H), 2.05 (dtd, J = 12.9, 5.2, 2.2 Hz, 1H), 1.77 (p, J = 6.5 Hz, 3H), 1.51 - 1.23 (m, 13H).

[0293] [Biological Examples] <Activity data of example compounds (Figures 1 to 5)> (Immunoblotting.) Proteins were extracted in RIPA assay buffer containing protease and phosphatase inhibitors. Extracts (30 μg) were separated by SDS / PAGE and electrophoretically transferred to Immun-Blot® PVDF membranes (Bio-Rad). Membranes were saturated in 3% nonfat dry milk or 3% BSA and, where indicated, probed overnight at 4° C. with antibodies against ERK5, BRD4, p-ERK5, MEK5, ERK1 / 2 and β-actin (1:1,000 dilution unless otherwise stated). We detected immune complexes by enhanced chemiluminescence using IgG conjugated to horseradish peroxidase as secondary anti-rabbit and anti-mouse antibodies (Abcam).

[0294] Figures 1-5 show Western blot data showing ERK5 levels in MDA 468 at different concentrations of Examples 1-12. A graphical representation of this data is provided to demonstrate expression relative to DMSO control. The graph on the right side of Figure 1 also includes the expression of ERK5 (lower line) and BRD4 (upper line).

[0295] Graphical representation of immunoblot signals: Densitometry of the bands of the proteins of interest on the immunoblots was measured using ImageJ. Protein levels were calculated relative to the loading control (b-actin) and are shown as fold increase relative to the control (vehicle treatment).

[0296] <Specificity test - OS1: 8-point dose response against three TNBC cell lines (Figure 8)> (material and method) (Immunoblotting.) We extracted proteins in RIPA assay buffer containing protease and phosphatase inhibitors. We separated extracts (30 μg) by SDS / PAGE and electrophoretically transferred them to Immun-Blot® PVDF membranes (Bio-Rad). Membranes were saturated in 3% nonfat dry milk or 3% BSA and probed overnight at 4° C. with antibodies against ERK5, P-ERK5, ERK1 / 2, BRD4, MEK5 and β-actin (1:1,000 dilution unless otherwise stated). We detected immune complexes by enhanced chemiluminescence using IgG conjugated to horseradish peroxidase as secondary anti-rabbit and anti-mouse antibodies (Abcam).

[0297] (Figure shows) The left panel is a Western blot image showing the relative expression of proteins in response to various doses of OS1, and the right panel is a graph quantifying the Western blot image to show ERK5, phospho-ERK5, ERK1 / 2 and BRD4 protein levels relative to the loading control β-actin.

[0298] The data shown in Figure 8 show that OS1 is specific and degrades >90% of ERK5 in various TNBC cell lines. OS1 has no off-target effects on structurally similar proteins (ERK1 / 2) or known off-targets of ERK5 inhibitors in the literature (BRD4). Although OS1 is most effective at 1 uM, a dose of 10 uM induces a hook effect.

[0299] At higher doses, OS1 also has kinase inhibitor activity, exemplified by a reduction in p-ERK5 on immunoblots, which is expected since the ERK5 targeting warhead is based on an ERK5 kinase inhibitor.

[0300] <Repeated administration of OS1 for up to 2 weeks (Figure 9)> (material and method) (Immunoblotting.) The inventors extracted proteins in RIPA assay buffer containing protease and phosphatase inhibitors. The inventors separated the extract (30 μg) by SDS / PAGE and transferred it electrophoretically to an Immun-Blot® PVDF membrane (Bio-Rad). The membrane was saturated in 3% non-fat dry milk or 3% BSA and probed overnight at 4 °C with antibodies against ERK5, BRD4, MEK5 and β-actin (1:1,000 dilution unless otherwise stated). The inventors detected immune complexes by enhanced chemiluminescence using IgG conjugated to horseradish peroxidase as secondary anti-rabbit and anti-mouse antibodies (Abcam).

[0301] (As shown in the figure) The data shown in Figure 9 show that repeated dosing of OS1 every 48 hours does not affect the specificity of OS1.

[0302] Repeated dosing was carried out for up to 2 weeks, which had no effect on either ERK1 / 2 (structurally similar kinases) or BRD4 (a known off-target of kinase inhibitors in the literature). MEK5, the upstream activator of ERK5, was also not affected by repeated dosing of OS1.

[0303] The inventors can now conclude that all data using OS1 result in a specific decrease in ERK5.

[0304] <Morphology of TNBC cells (Figure 10)> (Materials and methods) Cells were seeded and treated. The medium was aspirated and cells were washed with PBS and then fixed in 10% formalin for 10 min. Fixed cells were washed in PBS and then permeabilized with 0.1% (v / v) Triton-100 in PBS for 10 min. Cells were washed with PBS and non-specific binding sites were blocked by incubating with 1% BSA for 30 min. Targets of interest were identified by overnight incubation at 4°C with 100 μl of primary antibodies diluted in 1% BSA (see table). After washing with PBS, samples were further incubated with species-specific secondary antibodies conjugated to fluorescent tags (see antibody table) for 1 h at room temperature in the dark. Some samples were further incubated with 100 μl of 1:200 phalloidin (Invitrogen, A12381) in 1% BSA for 2 h at room temperature to identify actin filament structures. EZ-slide casings were disassembled as described in the manufacturer's instructions and slides were washed in distilled H2O. Samples were incubated with a drop of Mounting Medium (abcam) containing DAPI for 5 minutes at room temperature in the dark to visualize nuclei. A cover slip was added to each slide and allowed to dry at room temperature. Images were acquired on a 3D-Histech Pannoramic-250 microscope slide-scanner using a 20x / 0.80 Plan Apochromat objective (Zeiss) and DAPI, FITC and TRITC filter sets. Snapshots of the slide-scan were taken using Case Viewer software (3D-Histech). Images were then processed and analyzed using ImageJ.

[0305] (Figure shows) Immunofluorescence staining in three triple-negative breast cancer cell lines: MDA-MB-231, MDA-MB-468, and SUM159.

[0306] Figure 10 shows that OS1 affects the morphology of TNBC cells, whereas AX15836 (kinase inhibitor) does not affect the morphology of TNBC cells. This data is consistent with data from shERK5 and CRISPR studies in TNBC, where reduction of ERK5 leads to morphological changes. The morphological changes observed here indicate a reduction in metastatic potential and metastatic potential.

[0307] It is reaffirmed that OS1 efficiently degrades ERK5, as shown by the reduction in ERK5 staining (green) in OS1-treated cells.

[0308] Treatment with OS1 induces morphological changes in TNBC cell lines that cannot be recapitulated with a specific kinase inhibitor (AX15836).

[0309] These morphological changes are consistent with studies in TNBC where EKR5 is knocked down or ablated via genetic and siRNA approaches.

[0310] The observed morphological changes are consistent with a less migratory, less metastatic phenotype in TNBC cells. Similar morphological changes to those observed here occurred in siRNA / CRISPR knockdown ERK5 studies, which directly mapped to an anti-metastatic phenotype in preclinical in vivo models of TNBC. Therefore, we can infer that OS1 has an anti-metastatic effect in vivo.

[0311] In contrast, specific kinase inhibitors fail to recapitulate this phenotype and may be ineffective in preventing TNBC metastasis in vivo.

[0312] Therefore, a degradative approach is the most suitable way to target ERK5 for therapeutic gain in TNBC.

[0313] <qRT-PCR in response to 24-hour OS1 treatment (Figure 11)> (material and method) qRT-PCR: Total RNA was isolated from cells using TRIZOL and / or miRNeasy mini kits (Qiagen). We performed cDNA synthesis as previously described by Green, D., Eyre, H., Singh, A. et al. (Targeting the MAPK7 / MMP9 axis for metastasis in primary bone cancer. Oncogene 39, 5553-5569 (2020)). We performed qPCR using SYBR Green I core kits (Eurogentec). PCR products were detected with an ABI PRISM® 7700 Sequence Detection System (Thermo Fisher Scientific). We analyzed the results using the 2-ΔΔG method. Gene expression was normalized to PGK1 or ACTB.

[0314] (Figure shows) Relative mRNA levels compared to internal controls PGK1 or ACTB in three triple-negative breast cancer cell lines: MDA-MB-231, MDA-MB-468 and SUM159.

[0315] The data shown in FIG. 11 demonstrate that reduction of ERK5 by OS1 results in decreased expression of genes that promote EMT, angiogenesis and tumor-promoting inflammation.

[0316] Treatment with OS1, but not a specific ERK5 kinase inhibitor (AX15836), induces a decrease in the expression of genes that promote EMT, migration and metastatic behavior (N-cadherin, cytokeratin and B1-integrin), angiogenesis (VEGF) and tumor-promoting inflammation (IL6, IL1b).

[0317] Conversely, ERK5 degradation (by OS1) leads to increased expression of genes that block EMT, migration and metastatic behavior (E-cadherin).

[0318] A dose of 1 μM OS1 is most effective in affecting gene expression, and thus the inventors conclude that a reduction of more than 80% of the ERK5 protein is required to elicit the maximum phenotypic effect in TNBC cell lines.

[0319] <Comparison of OS1 and OS11 with Example 7 of International Publication No. 2021 / 061894 (Figures 12 and 13)> (Materials and Methods) (Immunoblotting) The inventors extracted proteins in RIPA assay buffer containing protease and phosphatase inhibitors. The inventors separated the extract (30 μg) by SDS / PAGE and transferred it electrophoretically to an Immun-Blot® PVDF membrane (Bio-Rad). The membrane was saturated in 3% non-fat dry milk or 3% BSA and probed overnight at 4 °C with antibodies against ERK5, BRD4, MEK5 and β-actin (1:1,000 dilution unless otherwise stated). The inventors detected immune complexes by enhanced chemiluminescence using IgG conjugated to horseradish peroxidase as secondary anti-rabbit and anti-mouse antibodies (Abcam).

[0320] (What the Figures Show) The data shown in Figures 12 and 13 show Western blots of ERK5 and BRD4 levels relative to b-actin 48 hours after treatment with single doses of ERK5-PROTACs: OS1 (Figure 12), OS11 (Figure 13) and Example 7 of WO 2021 / 061894 (hereafter referred to as "Comparative Example 7" (Comp Ex 7)) in MDA-MB-468 cells. OS1 and OS11 degrade EKR5 at lower concentrations than Comparative Example 7. OS1 is effective at degrading ERK5 at a dose of 0.1 μM and OS11 at 0.01 μM. In contrast, a dose of 5 μM of Comparative Example 7 is required to achieve similar ERK5 degradation as 0.1 μM OS1 or 0.01 μM OS11. OS1 or OS11 do not cause degradation of a known off-target of ERK5-targeting agents: BRD4. However, Comparative Example 7 causes simultaneous degradation of BRD4 at the dose required to degrade ERK5 (5 μM Comparative Example 7). Thus, OS1 and OS11 are more potent and specific than the ERK5-PROTAC compound Comparative Example 7.

[0321] [Conclusion] The biological examples described herein demonstrate that the ERK5-PROTAC approach is feasible. Compounds according to the invention are specific and potent for ERK5. Furthermore, the data demonstrate: The compounds of the present invention are capable of inducing anti-migratory and anti-metastatic phenotypes in TNBC cells, but are unable to inhibit kinases. The compounds of the present invention can block tumor-promoting inflammatory signaling but not kinase inhibition in TNBC cells. The compounds of the present invention, unlike ERK5-kinase inhibitors, are able to reproduce the anti-cancer effects seen in preclinical cancer studies using genetic or siRNA approaches targeting ERK5. · The ERK5 degrading approach is the most suitable way to target ERK5 for therapeutic gain in multiple cancers with unmet need.

[0322] <In Vivo Efficacy of OS11 in an Immune-Competent Model of TNBC> (Materials and Methods) (In Vivo Efficacy Test) The mouse TNBC cell line EMT6 was orthotopically transplanted (into the mammary fat pad) into 8- to 10-week-old Balb / c mice. Tumors were measured with calipers, and when the tumors reached 100-150 mm 3 , the mice were randomized into 4 treatment groups: vehicle control, anti-PD1 alone, OS11 alone (20 mg / kg), and combination treatment. The experiment was performed in a blinded manner. The tumors were grown to an endpoint <1000 mm 3 unless a harmful phenotype due to metastasis that required an earlier endpoint was observed. At the endpoint, terminal blood samples and tumors were collected for analysis.

[0323] (Immunoblotting) We extracted proteins from terminal blood samples and ex vivo biopsies of tumors into RIPA assay buffer containing protease and phosphatase inhibitors. We separated the extracts (30 μg) by SDS / PAGE and transferred them electrophoretically to Immun-Blot® PVDF membranes (Bio-Rad). The membranes were saturated in 3% non-fat dry milk or 3% BSA and probed overnight at 4°C with antibodies against ERK5 and β-actin (1:1,000 dilution unless otherwise stated). We detected immune complexes by enhanced chemiluminescence using IgG conjugated to horseradish peroxidase as secondary anti-rabbit and anti-mouse antibodies (Abcam).

[0324] (What the Figures Show) The data shown in Figure 14A demonstrate the effective knockdown of ERK5 by OS11 in vivo in tumor compartments and PBMCs (derived from terminal blood samples). The data shown in Figure 14B demonstrate that OS11 has an anti-tumor effect equal to that of anti-PD1, and that combination treatment of OS11 with anti-PD1 has no further effect beyond that of either drug alone.

[0325] [Conclusion] Compounds of the present invention are effective in degrading ERK5 in vivo in tumor compartments and peripheral blood, and are effective as anti-cancer agents similar to PD1-inhibitors in orthotopic immunocompetent models of TNBC.

Claims

1. The following structural formula (I): 【Chemistry 1】 [In the formula, R １ is -S(O) ２ -(1-3C)alkyl; R ２ is (1-4C)alkoxy; R ３ is selected from hydrogen, fluoro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; X １ is N or CH; L is of the formula: 【Chemistry 2】 (In the formula, 【Chemistry 3】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 4】 represents the point of attachment to Q; n is 0 or 1; L １ is a (2-10C) alkylene linker or of formula - [CH ２ CH ２ -O] １～３ - [CH ２ ] １～３ - is a PEG chain having the formula: Y １ and Y ２ teeth: Ethynylene group ( 【Chemistry 5】 ）； Ethylene group (-CH=CH-); -CH ２ -O-; -CH ２ -NH-; or -CH ２ -CH ２ - (which together form Q: 【Chemistry 6】 (In the formula, 【Chemistry 7】 Is Y ２ or represents the point of attachment to the group L; X ２ is -CH ２ - or -C(O)-; １ and Y ２ is an ethynylene group ( 【Chemistry 8】 ) together, X ２ is not —C(O)—. The compound, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

2. R １ But -S(O) ２ -CH ３ 2. The compound of claim 1, wherein:

3. R ２ is (1-3C)alkoxy; or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

4. R ２ The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein is ethoxy.

5. R ３ A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein is selected from hydrogen, fluoro or methyl.

6. R ３ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein is hydrogen.

7. X １ The compound according to any one of claims 1 to 6, wherein is N, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

8. The following structural formula (Ia): 【Chemistry 9】 [0023] wherein L and Q are as defined in claim 1. [0024] or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

9. L is of the formula: 【Chemistry 10】 [In the formula, 【Chemistry 11】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 12】 represents the point of attachment to Q; n is 0 or 1; L １ is a (2-8C) alkylene linker or of formula - [CH ２ CH ２ -O] １～３ - [CH ２ ] １～２ - is a PEG chain having the formula: Y １ and Y ２ teeth: Ethynylene group ( 【Chemistry 13】 ）； -CH ２ -O-; -CH ２ -NH-; or -CH ２ -CH ２ - or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

10. L is of the formula: 【Chemistry 14】 [In the formula, 【Chemistry 15】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 16】 represents the point of attachment to Q; n is 0 or 1; L １ is a (2-8C) alkylene linker or of formula - [CH ２ CH ２ -O] １～２ - [CH ２ ] １～２ - is a PEG chain having the formula: Y １ and Y ２ teeth: Ethynylene group ( 【Chemistry 17】 ）； -CH ２ -O-; -CH ２ -NH-; or -CH ２ -CH ２ - or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

11. L is of the formula: 【Chemistry 18】 [In the formula, 【Chemistry 19】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 20】 represents the point of attachment to Q; n is 0 or 1; L １ is a (2-8C)alkylene linker; Y １ and Y ２ teeth: Ethynylene group ( 【Chemistry 21】 ）； -CH ２ -O-; -CH ２ -NH-; or -CH ２ -CH ２ - or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

12. L is of the formula: 【Chemical 22】 [In the formula, 【Chemistry 23】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 24】 represents the point of attachment to Q; n is 0; L １ is a (2-8C) alkylene linker or of formula - [CH ２ CH ２ -O] １～２ - [CH ２ ] １～２ - is a PEG chain having the formula: Y １ and Y ２ teeth: Ethynylene group ( 【Chemistry 25】 ）； -CH ２ -O-; -CH ２ -NH-; or -CH ２ -CH ２ - or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

13. L is of the formula: 【Chemistry 26】 [In the formula, 【Chemistry 27】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 28】 represents the point of attachment to Q; n is 0 or 1; L １ is a (2-8C) alkylene linker or of formula - [CH ２ CH ２ -O] １～２ - [CH ２ ] １～２ - is a PEG chain having the formula: Y １ and Y ２ teeth: Ethynylene group ( 【Chemical Formula 29】 ） or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

14. L is of the formula: 【Chemistry 30】 [In the formula, 【Chemistry 31】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 32】 represents the point of attachment to Q; n is 0; L １ is a (3-8C)alkylene linker; Y １ and Y ２ teeth: Ethynylene group ( 【Chemical 33】 ）； -CH ２ -O-; -CH ２ -NH-; or -CH ２ -CH ２ - or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

15. L is of the formula: 【Chemical 34】 [In the formula, 【Chemistry 35】 represents the point of attachment to the N atom of the piperazine ring; 【Chemical 36】 represents the point of attachment to Q; n is 0; L １ is a (3-8C)alkylene linker; Y １ and Y ２ teeth: Ethynylene group ( 【Chemical 37】 ） or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

16. L is of the formula: 【Chemical 38】 [In the formula, 【Chemical Formula 39】 represents the point of attachment to the N atom of the piperazine ring; 【Chemistry 40】 represents the point of attachment to Q; n is 0; L １ is a (5-8C)alkylene linker; Y １ and Y ２ teeth: Ethynylene group ( 【Chemistry 41】 ） or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

17. L is: 【Chemistry 42】 【change】 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein the linker has a formula selected from:

18. Q: 【Chemistry 43】 [In the formula, X ２ is as defined in claim 1. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, selected from:

19. Q: 【Chemistry 44】 [In the formula, X ２ is as defined in claim 1. or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

20. X ２ But -CH ２ 20. The compound of any one of claims 1 to 19, wherein: -, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

21. 2-(2,6-dioxopiperidin-3-yl)-4-(5-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)pentyl)isoindoline-1,3-dione; 3-(4-(5-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(7-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hexyl)amino)isoindoline-1,3-dione; 3-(4-(3-(2-(2-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(8-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(9-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)non-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)hexyl)oxy)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)butoxy)isoindoline-1,3-dione; 3-(4-(10-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)dec-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((8-(4-(1-(3-ethoxy-4-((5-methyl-11-(methylsulfonyl)-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)octyl)oxy)isoindoline-1,3-dione; or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

22. A pharmaceutical composition comprising a compound according to claims 1 to 21, or a pharma- ceutically acceptable salt or solvate thereof, in admixture with a pharma- ceutically acceptable diluent or carrier.

23. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22, for use in therapy.

24. a) fibrotic diseases, e.g. wound healing disorders, pulmonary fibrosis, b) inflammatory diseases, such as psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22, for use in the treatment of, optionally in the treatment of, cancer.

25. In patients in need of such treatment, a) fibrotic diseases, e.g. wound healing disorders, pulmonary fibrosis, b) inflammatory diseases, such as psoriasis, asthma, c) proliferative conditions, e.g., cancers such as triple negative breast cancer, mesothelioma, primary bone cancer, glioblastoma, lung cancer, squamous cell carcinoma, etc. d) diabetes; e) pain, or f) Central nervous system (CNS) disorders, e.g., Parkinson's disease, dementia 23. A method for treating a patient suffering from rheumatoid arthritis, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 21, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22.

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