CN117384161A - 靶向降解cdk蛋白的化合物及其应用 - Google Patents
靶向降解cdk蛋白的化合物及其应用 Download PDFInfo
- Publication number
- CN117384161A CN117384161A CN202210788227.1A CN202210788227A CN117384161A CN 117384161 A CN117384161 A CN 117384161A CN 202210788227 A CN202210788227 A CN 202210788227A CN 117384161 A CN117384161 A CN 117384161A
- Authority
- CN
- China
- Prior art keywords
- substituted
- unsubstituted
- compound
- group
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 99
- 102000003903 Cyclin-dependent kinases Human genes 0.000 title claims abstract description 22
- 108090000266 Cyclin-dependent kinases Proteins 0.000 title claims abstract description 22
- 230000015556 catabolic process Effects 0.000 title abstract description 11
- 238000006731 degradation reaction Methods 0.000 title abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 239000012453 solvate Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 13
- 230000001404 mediated effect Effects 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 125000005647 linker group Chemical group 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000004193 piperazinyl group Chemical class 0.000 claims description 7
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000036541 health Effects 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 235000013305 food Nutrition 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical class [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 108091007914 CDKs Proteins 0.000 abstract description 36
- 230000000694 effects Effects 0.000 abstract description 12
- 230000000593 degrading effect Effects 0.000 abstract description 7
- 238000011865 proteolysis targeting chimera technique Methods 0.000 abstract description 3
- 108010026668 snake venom protein C activator Proteins 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 60
- 230000015572 biosynthetic process Effects 0.000 description 52
- 238000003786 synthesis reaction Methods 0.000 description 51
- -1 norcaryl Chemical group 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 37
- 206010028980 Neoplasm Diseases 0.000 description 32
- 239000007787 solid Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 230000022131 cell cycle Effects 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- OOIPDYWPGUHUJW-UHFFFAOYSA-N 8h-pteridin-7-one Chemical compound C1=NC=NC2=NC(O)=CN=C21 OOIPDYWPGUHUJW-UHFFFAOYSA-N 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 108050002653 Retinoblastoma protein Proteins 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 102000016736 Cyclin Human genes 0.000 description 5
- 108050006400 Cyclin Proteins 0.000 description 5
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 5
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010060862 Prostate cancer Diseases 0.000 description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960000688 pomalidomide Drugs 0.000 description 5
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000017854 proteolysis Effects 0.000 description 5
- 230000022983 regulation of cell cycle Effects 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 4
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 201000005787 hematologic cancer Diseases 0.000 description 4
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 3
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 3
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 3
- 108010093502 E2F Transcription Factors Proteins 0.000 description 3
- 102000001388 E2F Transcription Factors Human genes 0.000 description 3
- 206010014733 Endometrial cancer Diseases 0.000 description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000010190 G1 phase Effects 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 230000018199 S phase Effects 0.000 description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003172 aldehyde group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 3
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 3
- 229960004942 lenalidomide Drugs 0.000 description 3
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- TWOVEQMWQFKDIL-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-[2-(2-hydroxyethoxy)ethylamino]isoindole-1,3-dione Chemical compound O=C1NC(CCC1N1C(C2=CC=CC(=C2C1=O)NCCOCCO)=O)=O TWOVEQMWQFKDIL-UHFFFAOYSA-N 0.000 description 2
- CRAUTELYXAAAPW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione Chemical compound O=C1C=2C(F)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O CRAUTELYXAAAPW-UHFFFAOYSA-N 0.000 description 2
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 description 2
- WCBURNWVRFRXTK-UHFFFAOYSA-N 2-chloro-n-cyclopentyl-5-nitropyrimidin-4-amine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1NC1CCCC1 WCBURNWVRFRXTK-UHFFFAOYSA-N 0.000 description 2
- WYIGFEKILOYHCT-UHFFFAOYSA-N 4-(2-aminoethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound O=C1C=2C(NCCN)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O WYIGFEKILOYHCT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- FXHXURWAQHREPY-UHFFFAOYSA-N 8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)Nc1cccc2C(=O)N(C3CCC(=O)NC3=O)C(=O)c12 FXHXURWAQHREPY-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 229940126074 CDK kinase inhibitor Drugs 0.000 description 2
- 101100439046 Caenorhabditis elegans cdk-2 gene Proteins 0.000 description 2
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 102000003910 Cyclin D Human genes 0.000 description 2
- 108090000259 Cyclin D Proteins 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- 102100034770 Cyclin-dependent kinase inhibitor 3 Human genes 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 206010016935 Follicular thyroid cancer Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000010337 G2 phase Effects 0.000 description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000945639 Homo sapiens Cyclin-dependent kinase inhibitor 3 Proteins 0.000 description 2
- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 206010023347 Keratoacanthoma Diseases 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 208000010505 Nose Neoplasms Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 102100032783 Protein cereblon Human genes 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 201000010208 Seminoma Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 206010043276 Teratoma Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 201000010175 gallbladder cancer Diseases 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 208000037830 nasal cancer Diseases 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 230000005740 tumor formation Effects 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- TZZDVPMABRWKIZ-XMOGEVODSA-N (3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound OC=1C=C2CC[C@@H]([C@@H](C2=CC=1)C1=CC=C(C=C1)N1CCC(CC1)CN1CCN(CC1)C=1C=C2CN(C(C2=CC=1)=O)[C@@H]1C(NC(CC1)=O)=O)C1=CC=CC=C1 TZZDVPMABRWKIZ-XMOGEVODSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- VWXIHLCLIOQWRA-UHFFFAOYSA-N 1h-pteridin-2-one Chemical class N1=CC=NC2=NC(O)=NC=C21 VWXIHLCLIOQWRA-UHFFFAOYSA-N 0.000 description 1
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 1
- ISOVLZMZYIAHFW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-(2-hydroxyethoxy)ethoxy]ethylamino]isoindole-1,3-dione Chemical compound OCCOCCOCCNC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O ISOVLZMZYIAHFW-UHFFFAOYSA-N 0.000 description 1
- MPQLCQKBYRSPNA-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione Chemical compound O=C1C2=CC(F)=CC=C2C(=O)N1C1CCC(=O)NC1=O MPQLCQKBYRSPNA-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical compound CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- KMGOFKGAYSFPGS-UHFFFAOYSA-N 4-(4-aminobutylamino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound NCCCCNC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O KMGOFKGAYSFPGS-UHFFFAOYSA-N 0.000 description 1
- WNXNUPJZWYOKMW-UHFFFAOYSA-N 5-bromopentanoic acid Chemical compound OC(=O)CCCCBr WNXNUPJZWYOKMW-UHFFFAOYSA-N 0.000 description 1
- NVRVNSHHLPQGCU-UHFFFAOYSA-N 6-bromohexanoic acid Chemical compound OC(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BYJLIXXRIFPQTH-UHFFFAOYSA-N 8-cyclopentyl-2-(4-piperazin-1-ylanilino)pteridin-7-one Chemical compound N1=C2N(C3CCCC3)C(=O)C=NC2=CN=C1NC(C=C1)=CC=C1N1CCNCC1 BYJLIXXRIFPQTH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101150108519 CDK4 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000003909 Cyclin E Human genes 0.000 description 1
- 108090000257 Cyclin E Proteins 0.000 description 1
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 1
- 102100023263 Cyclin-dependent kinase 10 Human genes 0.000 description 1
- 102100033245 Cyclin-dependent kinase 16 Human genes 0.000 description 1
- 102100033145 Cyclin-dependent kinase 19 Human genes 0.000 description 1
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 230000035519 G0 Phase Effects 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000908138 Homo sapiens Cyclin-dependent kinase 10 Proteins 0.000 description 1
- 101000944345 Homo sapiens Cyclin-dependent kinase 19 Proteins 0.000 description 1
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101000980932 Homo sapiens Cyclin-dependent kinase inhibitor 2A Proteins 0.000 description 1
- 101000624643 Homo sapiens M-phase inducer phosphatase 3 Proteins 0.000 description 1
- 101000733249 Homo sapiens Tumor suppressor ARF Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CLCTZVRHDOAUGJ-UHFFFAOYSA-N N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidin-1-yl]pyridazine-3-carboxamide Chemical compound FC1=CC2=C(C=C1N1CCN(CC3CCN(CC3)C3=CC=C(N=N3)C(=O)NC3CCC(CC3)OC3=CC(Cl)=C(C=C3)C#N)CC1)C(=O)N(C1CCC(=O)NC1=O)C2=O CLCTZVRHDOAUGJ-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- HHAIXNHKPAADOF-UHFFFAOYSA-N ONC(CO)(CO)CO.[Na] Chemical compound ONC(CO)(CO)CO.[Na] HHAIXNHKPAADOF-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 101150040313 Wee1 gene Proteins 0.000 description 1
- XQKRPEDJRVOOAA-UHFFFAOYSA-J [Mg+2].[Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O Chemical compound [Mg+2].[Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XQKRPEDJRVOOAA-UHFFFAOYSA-J 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 108010072268 cyclin-dependent kinase-activating kinase Proteins 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005482 norpinyl group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- RXFHRKPNLPBDGE-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(N)C=C1 RXFHRKPNLPBDGE-UHFFFAOYSA-N 0.000 description 1
- FPBMKRCNELOZRV-UHFFFAOYSA-N tert-butyl 4-[4-[(8-cyclopentyl-7-oxopteridin-2-yl)amino]phenyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(C=C1)=CC=C1NC1=NC=C(N=CC(=O)N2C3CCCC3)C2=N1 FPBMKRCNELOZRV-UHFFFAOYSA-N 0.000 description 1
- BIQRPUMMHJKVBI-UHFFFAOYSA-N tert-butyl 4-[4-[[4-(cyclopentylamino)-5-nitropyrimidin-2-yl]amino]phenyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(C=C1)=CC=C1NC1=NC=C([N+]([O-])=O)C(NC2CCCC2)=N1 BIQRPUMMHJKVBI-UHFFFAOYSA-N 0.000 description 1
- SECHWJPNVLPBQP-UHFFFAOYSA-N tert-butyl 4-[4-[[5-amino-4-(cyclopentylamino)pyrimidin-2-yl]amino]phenyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(C=C1)=CC=C1NC1=NC=C(N)C(NC2CCCC2)=N1 SECHWJPNVLPBQP-UHFFFAOYSA-N 0.000 description 1
- CTBFCHXDKXTELK-UHFFFAOYSA-N tert-butyl N-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCNC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O CTBFCHXDKXTELK-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了式(I)所示化合物，或其异构体、药学上可接受的盐、水合物、溶剂化物或前药。本发明的化合物是对CDK蛋白激酶具有优异降解活性的PROTAC分子。本发明的化合物为开发能靶向降解CDK的药物奠定了物质基础，从而具备极大的产业化和商品化前景。
Description
技术领域
本发明涉及药物化学领域。具体地说，本发明涉及靶向降解CDK蛋白，例如CDK4/6蛋白的化合物、其制备方法以及在治疗CDK蛋白介导的疾病中的应用。
背景技术
2018年全球肿瘤统计数据显示，全球估计有1819万癌症新增病例以及960万癌症死亡病例。仅我国每天约有1万人确诊癌症，相当于平均每分钟就有7个人确诊癌症。研究发现，在多种癌症的形成和发展中，CDK4/6都扮演着重要的角色。因此，CDK4/6靶点也就成为癌症靶向治疗的重要作用靶标，尤其是针对乳腺癌、肺癌、前列腺癌等疾病，靶向CDK4/6激酶都有很好的治疗潜力。
近年来，靶向蛋白质降解(Proteolysis Targeting Chimeras，PROTACs)已成为一种新兴的治疗手段。PROTACs是利用一种双功能小分子，在细胞内PROTACs可以同时与靶蛋白及E3结合，使本来不能与E3结合的靶蛋白泛素化，进而被蛋白酶体识别并降解。自第一个PROTAC分子报道以来，许多E3连接酶，例如von Hippel-Lindau(VHL)，CRBN(cereblon)，Mourine Double Mininute 2(MDM2)和细胞凋亡蛋白1(cIAP1)抑制剂，已被用于设计靶向PROTAC的分子不同的蛋白质。
与经典的抑制剂相比，PROTAC分子几乎可以完全消除靶蛋白的功能。此外，PROTAC分子通常不需要与目标分子牢固结合和即可实现蛋白质降解，因此，可以有效的避免药物诱导的抗性突变的发生。目前为止，PROTAC已有针对多个靶点的药物进入临床实验。目前处于临床一期的两个PROTAC药物ARV-110(靶向雄激素受体，治疗前列腺癌)和ARV-471(靶向雌激素受体，治疗乳腺癌)，都展现了积极的疗效数据。这充分的反应出PROTAC技术在克服耐药和靶向不可成药靶点方面具有非常大的潜力。
因此，运用蛋白降解靶向嵌合体(PROTAC)技术，研究开发可以降解CDK4/6蛋白的新型靶向药物具有重大的临床意义和应用背景。
发明内容
本发明的目的是提供能够靶向降解CDK4/6蛋白的化合物，及其制备方法和应用。本发明的化合物不仅具有优异的CDK4/6蛋白降解作用和抗肿瘤活性，对人体毒副作用小，因此可用于制备抗肿瘤药物。
本发明的另一目的是提供包含上述化合物的药物组合物。
本发明还有一目的是提供上述化合物在制备治疗CDK4/6蛋白介导的疾病的药物中的用途。
在第一方面，本发明提供式(I)所示的化合物，或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
其中，R1选自下组：未取代的或取代的(优选卤素取代的)C1-C10直链或支链烷基、未取代的或取代的(优选卤素取代的)的C3-C8环烷基、未取代或取代的C3-C8杂环基、未取代或取代的C5-C10芳基、未取代或取代的C5-C10芳杂环基；
R2选自下组：氢、乙酰基、氰基、未取代或取代的C1-C10烷基、未取代或取代的C3-C8环烷基、未取代或取代的C3-C8杂环基、未取代或取代的C5-C10芳基、未取代或取代的C5-C10芳杂环基、未取代或取代的C1-C10烷基酰基、未取代或取代的酰胺基；
R3选自下组：C1-C8烷基或C1-C8氨基烷基取代的伯氨基或仲胺基、C3-C6环烷基取代的伯氨基、N上未取代或有C1-C6烷基取代的哌嗪基；
X为取代或未取代的CH或N；
Linker如下式所示：
m为0-12，优选1-8，更优选1-6，最优选1-3的整数；
n为0-6，优选1-4的整数；
Y为羰基或取代或未取代的CH2。
在优选的实施方式中，所述E3泛素连接酶配体是来那度胺或泊马度胺。
在具体的实施方式中，所述化合物是式(II)所示化合物：
其中，R1、R2、R3、X、Linker、m和n如权利要求1所述；
Y为羰基或取代或未取代的CH2。
在具体的实施方式中，R1选自未取代或取代的(优选卤素取代的)甲基、乙基、叔丁基、异丙基或环戊烷基、或未取代的或在杂原子上有C1-C6取代基的C3-C8杂环基。
在具体的实施方式中，R2为乙酰基、取代或未取代的C5-C10芳杂环基，取代或未取代的酰胺基；
X为CH或N。
在优选的实施方式中，R2为乙酰基、呋喃环、酰胺基或氰基。
在具体的实施方式中，R3为C1-C8烷基取代的仲胺基或者N上未取代的或有C1-C3烷基取代的哌嗪基。
在优选的实施方式中，所述药学上可接受的盐包括：钾盐、钠盐、盐酸盐、甲酸盐、三氟醋酸盐、磷酸盐和硫酸盐。
在具体的实施方式中，本发明提供选自下组的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
在具体的实施方式中，R1是未取代的或取代的(优选卤素取代的)的C3-C8环烷基(优选C4-C6环烷基)；
R2是氢；
R3是N上未取代或有C1-C6烷基取代的哌嗪基；
X为取代或未取代的CH；
Linker如下式所示：
m为1-3的整数；
n为1-4的整数；
Y为羰基。
在具体的实施方式中，本发明提供选自下组的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
在第二方面，本发明提供一种药物组合物，其特征在于，含有第一方面所述的化合物或其异构体、药学上可接受的盐、水合物、溶剂化物或前药，以及药学上可接受的载体或赋形剂。
在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
在第三方面，本发明提供第一方面所述的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药在制备治疗CDK蛋白激酶介导的疾病的药物或在制备食品或保健品中的用途。
在优选的实施方式中，所述CDK蛋白激酶是CDK4/6，即细胞周期依赖性激酶4/6。
在优选的实施方式中，所述CDK蛋白激酶介导的疾病是癌症。
在优选的实施方式中，所述癌症选自下组：膀胱癌、乳腺癌、结肠癌、直肠癌、肾癌、表皮癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌、皮肤癌、淋巴系的造血细胞肿瘤、髓系造血细胞肿瘤、甲状腺滤泡癌、源于间质细胞肿瘤、中枢或周围神经系统肿瘤、黑素瘤、神经胶质瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘细胞瘤、甲状腺滤泡癌、卡波西肉瘤、肾细胞癌、子宫内膜癌、头颈部鳞状细胞癌、急性髓系白血病，或者其他CDK亚型参与调控的癌症。
在优选的实施方式中，所述淋巴系的造血细胞肿瘤选自白血病、急性淋巴性白血病、慢性淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤或伯基特氏淋巴瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了化合物7a-7f对CDK4/6蛋白的降解情况。
具体实施方式
发明人经过广泛而深入的研究，发现一批结构全新的PROTAC分子，这些化合物能够降解CDK蛋白，对CDK激酶的降解活性的DC50值达到nM级别，在此基础上完成了本发明。
术语定义
本文所用的科学和技术术语与本发明所属领域的技术人员常规理解得相同或相似。为清晰起见，对本文中涉及到的一些基团定义如下：
本发明中，“烷基”是指直链或支链饱和烃基基团。在一些实施方案中，烷基基团可具有1至10个碳原子(例如1至8个碳原子)。烷基基团的实例包括甲基(Me)、乙基(Et)、丙基(例如，正丙基和异丙基)、丁基(例如，正丁基、异丁基、仲丁基、叔丁基)、戊基基团(例如，正戊基、异戊基、新戊基)、已基(例如，正已基及其异构体)等。低级烷基基团一般最多有4个碳原子。低级烷基基团的实例包括甲基、乙基、内基(例如正丙基和异丙基)和丁基基团(例如正丁基、异丁基、仲丁基、叔丁基)。在一个实施方案中，一个烷基基团或两个或多个烷基基团可形成桥连的烷基基团；即其中烷基基团经另一个基团连接(特别显示于环状基团)，通过烷基链桥连形成环，即形成桥连的稠合环。
本发明中，“环烷基”是指非芳香碳环基团，包括环状烷基、链烯基和炔基基团。环烷基基团可以是单环(例如环已基)或多环(例如，包含稠合、桥连和/或螺环体系)，其中碳原子位于环体系内部或外部。环烷基基团作为整体可具有3至14个环原子(例如，3至8个碳原子用于单环环烷基基团和7至14个碳原子用于多环环烷基基团)。环烷基基团的任何适宜环上位置可与所定义的化学结构共价连接。环烷基基团的实例包括环丙基、环丁基、环戊基、环已基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、冰片基、Norpinyl、Norcaryl、金刚烷基和螺[4.5]癸基，及其同系物、异构体等。
本发明中，“杂环基”包括但不限于含有1-3个选自O、S或N的杂原子的C3-C8杂环基，例如5元或6元杂环基团，包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基等。
本发明中，“芳基”指含有6到14个碳原子，例如5-10个碳原子的单环、双环或三环芳族基团，包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。芳基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6烷基、氰基、硝基、氨基、酰胺基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基等、杂环基或杂芳基等。
本发明中，“芳杂环基”是指含有5-14个，例如5-10个环原子，并且有6个、10个或14个电子在环体系上共用。而且所含环原子是碳原子和选自氧、氮、或硫的1-3个杂原子。有用的芳杂环基包括哌嗪基、吗啉基、哌啶基、吡咯烷基、噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、吡啶基、包括但不限制于嘧啶基等。芳杂环基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本发明中，“酰氨基”指结构式为“-R’-NH-C(O)-R”的基团，其中，R’可选自氢或烷基，R可选自烷基、链烯基、炔基、被NRcRd取代的烷基、被NRcRd取代的链烯基和NRcRd取代的炔基、被卤素取代的烷基、被氰基取代的链烯基，其中，Rc和Rd可选自烷基和链烯基。
本文中，“酰基”是指-CHO所示基团。类似地，本文中的“烷基酰基”或“芳基酰基”是指烷基或芳基与CHO相连形成的基团，所示基团通过烷基或芳基与化合物的其余部分相连。
本发明中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基，更优选为长1-3个碳原子的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、丙氧基等。烷氧基可以被1个或多个取代基取代，例如被卤素或卤代烷基取代。例如，烷氧基可以是被1-4个氟原子取代的烷基，或者烷基可以是被氟代烷基取代的烷基。
本发明中，“卤素”指氟、氯、溴或碘。
本发明中，“任选取代的”指其所修饰的取代基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
CDK蛋白激酶
在本发明中，“CDK”、“CDK蛋白”、“CDK激酶”或“CDK蛋白激酶”具有相同的含义，均是指细胞周期蛋白依赖性激酶。
细胞周期是指细胞从一次分裂完成开始到下一次分裂结束所经历的全过程，是细胞生命传递的基本过程。细胞周期主要分为4期：G期(First gap)、S期(Synthesis)、G2期(Second gap)、M期(Mitosis)。G1期主要为DNA的合成作准备，细胞主要合成RNA和核糖体；S期主要合成DNA以及DNA复制相关的酶，也合成组蛋白；G2期是有丝分裂的准备期，是DNA合成的后期，大量合成RNA以及微管蛋白等蛋白质；M期为细胞分裂期，又分为前、中、后、末期。经过一个细胞周期的过程，细胞会一分为二，母细胞会将遗传物质传递给子细胞，为后续的细胞分化、个体生长发育奠定基础。
细胞周期是一个连续的严格控制过程，受到以下三类蛋白调控：细胞周期蛋白(Cyclin)、细胞周期蛋白依赖性激酶(Cyclin dependent kinase，CDK)、细胞周期蛋白依赖性激酶抑制剂(Cyclin-dependent kinase inhibitor，CKI)。细胞周期异常是肿瘤发生的前提，主要表现为相关调节细胞周期的酶和蛋白的异常表达，从而导致细胞周期紊乱，细胞恶性增殖。细胞周期相关酶和蛋白的研究为肿瘤治疗提供理论基础。
细胞周期蛋白依赖性激酶，属于丝/苏氨酸蛋白激酶家族，是参与细胞周期调节的关键激酶。不同的CDK在细胞的不同阶段发挥着不同的作用。目前已经报道了有20多个不同的CDK亚型，根据CDK功能的不同，可以将其主要分为两大类。一类是参与细胞周期调控，主要包括CDK1、CDK2、CDK4、CDK6等；另一类是参与转录调节，主要包括CDK7、CDK8、CDK9、CDK10、CDK11等，当然也还有其他功能的，像CDK3、CDK5。
在哺乳动物细胞中，CDK单体没有活性，不同的CDK需要与相应的Cyclin结合后才能发挥作用。目前已确认与CDKs对应的12个Cyclins(A-L)。CDK可由一种CDK活化激酶CAK磷酸化后激活，CDK的激活是一个需要多种酶参与的、多步磷酸化的复杂过程，CAK则使得CDK的T-loop(如CDK1的T161、CDK2的T160)发生活化磷酸化，CDK核苷酸结合口袋处的残基(如CDK1的T14、CDK2的T15)可被Wee1磷酸化，阻止ATP结合从而失活，而这些抑制性磷酸化可被双特异性磷酸酶CDC25的作用下发生去磷酸化，从而使CDK再次处于激活状态。此外，CDK的活化也受到内源性抑制子抑制、活化及抑制磷酸化的调节。CDK内源抑制子(CDKInhibitor，CDKI)包括INK4和CIP/KIP两大家族，它们通过结合CDK单体或直接结合CDK-Cyclin复合物的磷酸化活化部位，限制其构象改变，抑制CDK的激酶活性。
随着CDK家族在癌症发生发展中的功能不断被研究，CDK一直被认为是一个较好的癌症治疗靶标。CDK4/6即细胞周期依赖性激酶4/6，是细胞周期中G1期重要的调控因子，能特异性的与Cyclin D结合形成复合物。CDK4是人类细胞中由位于12号染色体上的CDK4基因编码的一种蛋白激酶，与其他CDKs在结构上高度类似，都具有典型的双叶瓣结构。CDKs是细胞周期的引擎，在人细胞中CDK4及其高度同源的CDK6对细胞周期的调控具有关键作用，其涉及的Cyclin D-CDK4/6-INK4-Rb信号通路是调控G1-S期过渡的核心环节。CDK4/6是多条细胞信号通路共同的下游靶点，许多与癌症相关的信号通路会导致CDK4/6的特异性激活。在无外界信号刺激下，视网膜母细胞瘤蛋白(Retinoblastoma Protein，Rb)与转录因子E2F结合并抑制其活性，抑制增殖，使细胞处于G0期。在外界有丝分裂信号刺激下，会激活PI3K/Akt/mTOR信号通路，CDK4/6会与Cyclin D结合，形成CDK4/6-Cyclin D复合物，该复合物能够催化激活Rb蛋白并使其磷酸化，磷酸化的Rb蛋白释放出转录因子E2F，E2F诱导Cyclin E与CDK2结合并形成CDK2-Cyclin E复合物，该复合物使Rb蛋白磷酸化，从而充分释放出E2F转录因子，推进细胞周期由G1期进入S期，参与到DNA复制的进程中。
正常细胞的稳态得益于细胞周期正调控机制与负调控机制的平衡，而细胞周期调控的紊乱正是肿瘤细胞失控性生长的根本原因。细胞内分子调控网络的破坏和基因组的不稳定性导致细胞周期调控发生紊乱，成为肿瘤形成的关键因素。对人类肿瘤的分子分析表明，表达细胞周期调节分子的基因在人类肿瘤中经常发生突变。细胞周期异常是肿瘤形成和发展的一个标志。虽然CDKs很少在人类的癌症中突变，除了CDK4在小家族黑色素瘤发生过编码错误，但是大多数的肿瘤的CDKs上游调节蛋白或者下游底物蛋白突变或异常。因此，CDKs被认为是一个较好的癌症治疗靶标。
本发明的化合物
应用PROTAC技术，本发明人将7(8H)-蝶啶酮类化合物与E3泛素连接酶配体(例如来那度胺或泊马度胺)相连，同时设计了不同种类的Linker，从而构建了一系列PROTAC分子。本发明人对构建的PROTAC分子进行了结构确证和分子水平的降解活性测试，最终获得一批能够有效降解CDK激酶的化合物。
在具体的实施方式中，本发明提供式(I)所示的化合物，或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
式中，R1、R2、R3、X、Linker、m和n如上所述。
本领域技术人员可以为式(I)所示化合物选择合适的E3泛素连接酶配体，例如来那度胺或泊马度胺。因此，在优选的实施方式中，本发明的化合物可以是式(II)所示的化合物，或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
式中，Y可以是羰基或取代或未取代的CH2。
在进一步的优选实施方式中，本发明的化合物是选自下组的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
/>
更优选以下化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
/>
本领域技术人员知晓，本发明的化合物还应包括全部药学上可接受的同位素标记的化合物，其中一个或多个原子被有相同原子数的原子替换，但原子质量或质量数与通常见于自然中的原子质量或质量数不同。适于包含在本发明的化合物中的同位素包括氢的同位素，例如2H和3H，碳的同位素，例如11C、13C和14C，氮的同位素，例如13N和15N，氧的同位素，例如“15O、17O和18O”。
用较重的同位素例如氘即2H取代可提供某些治疗优势，其有更好的代谢稳定性，例如，体内半哀期增加或降低了剂量需求，并因此在某些情况下是优选的。
在本发明的化合物的基础上，本发明提供一种药物组合物。该组合物含有治疗有效量的本发明的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS，胺丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成用于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药的形式，用于治疗肿瘤和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。
本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类。
本发明的化合物或其药物组合物可用于治疗各种由CDK蛋白激酶介导的疾病。本文中，由CDK蛋白激酶介导的疾病为各种癌症。所述癌症包括但不限于：食管癌、肾细胞癌、胰腺癌、结肠癌、乳腺癌、肺癌、前列腺癌、卵巢癌、子宫内膜癌、头颈部鳞状细胞癌、急性髓系白血病和实体瘤。或者其他CDK亚型参与调控的癌症。
本发明的药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。
合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。
基于上述化合物和药物组合物，本发明进一步提供一种治疗CDK蛋白激酶介导的疾病的方法，该方法包括给予需要的对象以本发明的化合物或药物组合物。
给药方法包括但不限于本领域周知的各种给药方法，可根据患者的实际情况加以确定。这些方法包括但不限于肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药。
本发明也包括本发明化合物在制备预防或治疗CDK介导的疾病或抑制CDK活性的药物中的用途。
在一优选例中，所述CDK蛋白激酶介导的疾病是癌症。
在一优选例中，所述癌症选自下组：膀胱癌、乳腺癌、结肠癌、直肠癌、肾癌、表皮癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌、皮肤癌、淋巴系的造血细胞肿瘤、髓系造血细胞肿瘤、甲状腺滤泡癌、源于间质细胞肿瘤、中枢或周围神经系统肿瘤、黑素瘤、神经胶质瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘细胞瘤、甲状腺滤泡癌、卡波西肉瘤、肾细胞癌、子宫内膜癌、头颈部鳞状细胞癌、急性髓系白血病，或者其他CDK亚型参与调控的癌症。
在一优选例中，所述淋巴系的造血细胞肿瘤选自白血病、急性淋巴性白血病、慢性淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤或伯基特氏淋巴瘤。
本发明的优点：
1.本发明提供的化合物是一种结构全新的PROTAC分子；
2.本发明提供的化合物对CDK蛋白激酶具有优异的降解活性；
3.本发明提供的化合物为开发能靶向降解CDK的药物奠定了基础，具备极大的产业化和商品化前景以及市场价值，经济效益显著。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
材料与方法
具体合成方法如下：
实施例1.中间体2-6的合成
中间体2-氯-N-环戊基-5-硝基嘧啶-4-胺的合成
称取化合物2,4-二氯-5-硝基嘧啶(50.00g，259.00mmol)于1000mL三口烧瓶中，加入二氯甲烷(200mL)溶解，边搅拌边缓慢加入碳酸氢钠(43.50g，518.00mmol)，称取环戊胺(26.40g，311.00mmol)于恒压滴定漏斗中，加入二氯甲烷(50mL)溶解，冰浴下缓慢滴加到三口烧瓶中，滴加结束后，室温反应6h，TLC跟踪至原料反应完全，反应结束后，将产物用水萃取3次，收集有机相，用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相，减压浓缩除去溶剂，得到黄色固体化合物58.50g，收率93.5％。
1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.61(d,J＝7.6Hz,1H),4.53–4.44(m,1H),2.00–1.95(m,2H),1.75–1.69(m,2H),1.67–1.62(m,2H),1.60–1.56(m,2H).
中间体4-(4-((4-(环戊基氨基)-5-硝基嘧啶-2-基)氨基)苯基)哌嗪-1-羧酸叔丁酯的合成
称取化合物2-氯-N-环戊基-5-硝基嘧啶-4-胺(3.00g，0.01mol)于250mL三口烧瓶中，加入THF(20mL)溶解后，加入N,N-二甲基苯胺(1.80g，0.01mol)，称取4-(4-氨基苯基)哌嗪-1-羧酸叔丁酯(3.77g，0.01mol)放在恒压滴定漏斗中，加入异丙醇(30mL)溶解，缓慢滴加到三口烧瓶中，滴加结束后，80℃反应5h，TLC跟踪至原料反应完全，反应结束后自然冷却到室温，滴加乙酸调节pH，加入适量的水后，有沉淀析出，抽滤，收集滤饼，烘干，得到黄色固体化合物5.00g，收率83.8％。
中间体4-(4-((5-氨基-4-(环戊基氨基)嘧啶-2-基)氨基)苯基)哌嗪-1-羧酸叔丁酯的合成
称取化合物4-(4-((4-(环戊基氨基)-5-硝基嘧啶-2-基)氨基)苯基)哌嗪-1-羧酸叔丁酯(2.00g，4.14mmol)于250mL三口烧瓶中，加入甲醇(30mL)溶解后，加入10％的钯碳，H2置换，40℃反应3h，TLC跟踪至原料反应完全，反应结束后经硅藻土抽滤，收集滤液，将滤液减压浓缩，得到灰黑色固体化合物1.30g，产率69.1％。
1H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.50(d,J＝8.8Hz,2H),6.89(d,J＝8.7Hz,2H),6.71(s,1H),5.16(d,J＝6.9Hz,1H),4.40–4.30(m,1H),3.57(t,J＝5.1Hz,4H),3.04(t,J＝5.1Hz,4H),2.52(s,2H),2.13–2.06(m,2H),1.76–1.71(m,2H),1.67–1.62(m,2H),1.55–1.50(m,2H),1.48(s,9H).
中间体4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-羧酸叔丁酯的合成
称取化合物4-(4-((5-氨基-4-(环戊基氨基)嘧啶-2-基)氨基)苯基)哌嗪-1-羧酸叔丁酯(1.00g，2.20mmol)于微波反应管中，加入乙醇(4mL)溶解，加入乙醛酸乙酯(0.22g，2.20mmol)和乙酸(1mL)，50w，150PSI，100℃，45min。反应结束后，用氨水调节pH，用水萃取3次，收集有机相，用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝50/1，v/v)，得到黄色固体化合物0.20g，收率18.5％。
1H NMR(600MHz,Chloroform-d)δ7.98(s,1H),7.93(s,1H),7.53(d,J＝8.9Hz,2H),7.19(s,1H),6.91(d,J＝9.0Hz,2H),4.40–4.37(m,1H),3.58(t,J＝5.2Hz,4H),3.08(t,J＝5.2Hz,4H),2.13–2.06(m,2H),1.79–1.73(m,2H),1.67–1.61(m,2H),1.59–1.52(m,2H),1.48(s,9H).
中间体8-环戊基-2-((4-(哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮的合成
称取化合物4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-羧酸叔丁酯(200mg，0.41mmol)于50mL反应瓶中，加入二氯甲烷(4mL)溶解，冰浴下缓慢滴加TFA(1mL)，滴加结束后，室温反应1h，TLC跟踪至原料反应完全，反应结束后，减压浓缩除去溶剂，加入氨水研磨，得到黄色固体化合物105mg，收率66.0％。
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.77(s,2H),7.84(s,1H),7.55(d,J＝8.6Hz,2H),7.00(d,J＝8.8Hz,2H),5.71–5.55(m,1H),3.29(t,4H),3.25(t,4H),2.26–2.18(m,2H),1.92–1.83(m,2H),1.81–1.74(m,2H),1.60–1.55(m,2H),1.22(s,1H).
实施例2.Linker的合成
2-(2,6-二氧代哌啶-3-基)-4-((2-(2-羟基乙氧基)乙基)氨基)异吲哚啉-1,3-二酮的合成
称取化合物2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(500mg，1.81mmol)于50mL反应瓶中，加入DMF(5mL)溶解，缓慢加入二甘醇胺(8a)(228mg，2.17mmol)和N,N-二异丙基乙胺(1mL)，90℃下反应5h，TLC监测至原料反应完全，反应结束后，加入水淬灭反应，二氯甲烷萃取3次，饱和食盐水洗涤有机层，无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝100/1，v/v)，得到黄绿色固体化合物320mg，收率48.9％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.59(dd,J＝8.6,7.1Hz,1H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.61(t,J＝5.9Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.62(t,J＝5.3Hz,1H),3.62(t,J＝5.5Hz,2H),3.53–3.49(m,2H),3.48–3.44(m,4H),2.64–2.51(m,2H).
2-(2,6-二氧代哌啶-3-基)-4-((2-(2-羟基乙氧基)乙氧基)乙氨基)异吲哚啉-1,3-二酮的合成
/>
合成步骤参照10a的合成，得到黄绿色固体，收率50.2％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.58(t,1H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝7.1Hz,1H),6.61(t,J＝5.8Hz,1H),5.05(dd,J＝13.0,5.4Hz,1H),4.55(t,J＝5.4Hz,1H),3.62(t,J＝5.5Hz,2H),3.58–3.55(m,2H),3.55–3.52(m,2H),3.50–3.45(m,4H),3.41(t,J＝4.8Hz,2H),2.64–2.51(m,2H),2.08–1.97(m,2H).
2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基4-甲基苯磺酸酯的合成
称取化合物2-(2,6-二氧代哌啶-3-基)-4-((2-(2-羟基乙氧基)乙基)氨基)异吲哚啉-1,3-二酮(130mg，0.36mmol)于50mL反应瓶中，加入二氯甲烷(3mL)溶解，慢慢加入对甲苯磺酰氯(75mg，0.39mmol)和三乙胺(0.5mL)，30℃下反应6h，TLC监测至原料反应完全，反应结束后，水萃取三次，收集有机相，有机相用饱和食盐水洗涤，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝75/1，v/v)，得到黄色固体化合物70mg，收率37.8％。
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.76(d,J＝8.3Hz,2H),7.57(t,1H),7.44(d,J＝8.2Hz,2H),7.11(d,J＝8.5Hz,1H),7.05(d,J＝7.0Hz,1H),6.54(t,J＝6.2Hz,1H),5.06(dd,J＝13.0,5.4Hz,1H),4.14–4.11(m,2H),3.62–3.60(m,2H),3.52(t,J＝2.8Hz,2H),3.41–3.38(m,2H),2.37(s,3H),2.32–2.23(m,2H),2.11–1.89(m,2H).
2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯的合成
合成步骤参照12a的合成，得到黄色固体，收率39.8％。
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.76(d,J＝8.3Hz,2H),7.58(t,1H),7.45(d,J＝7.9Hz,2H),7.13(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.58(t,J＝5.8Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.11–4.08(m,2H),3.60–3.56(m,4H),3.51–3.43(m,6H),2.63–2.52(m,2H),2.39(s,3H),2.09–1.92(m,2H).
6-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺的合成
称取化合物6-溴己酸(1.00g，5.13mmol)于100mL单口烧瓶中，加入氯化亚砜(10mL)溶解，加入1滴DMF，80℃回流3h，减压浓缩除去溶剂，向反应体系中缓慢加入N,N-二异丙基乙胺(2mL)、四氢呋喃(15mL)和泊马度胺(1.40g，5.12mmol)，50℃反应6h，反应结束后，用大量的盐酸水溶液洗涤，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝150/1，v/v)纯化，得到白色固体化合物580mg，收率25.2％。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.73(s,1H),8.45(d,J＝8.4Hz,1H),7.83(t,J＝7.9Hz,1H),7.61(d,J＝7.3Hz,1H),5.14(dd,J＝12.7,5.5Hz,1H),2.31–2.25(m,2H),2.20–2.11(m,2H),1.86–1.78(m,2H),1.71–1.69(m,2H),1.63–1.60(m,2H),1.51–1.48(m,2H),1.39–1.36(m,2H).
7-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚酰胺的合成
合成步骤参照15a的合成，得到白色固体化合物，收率27.8％。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.71(s,1H),8.46(d,J＝8.4Hz,1H),7.83(t,J＝7.9Hz,1H),7.61(d,J＝7.3Hz,1H),5.14(dd,J＝12.8,5.4Hz,1H),3.58(dt,J＝40.2,6.6Hz,2H),2.67–2.51(m,2H),2.46(t,J＝7.4Hz,2H),1.85–1.68(m,2H),1.67–1.57(m,2H),1.47–1.30(m,4H).
8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-8-氧代辛酸的合成
称取化合物辛二酸(1g，5.74mmol)于100mL单口烧瓶中，加入氯化亚砜(10mL)溶解，加入1滴DMF，80℃回流2h，反应结束后，减压浓缩除去溶剂，向反应体系中缓慢滴加TEA(2mL)、二氯甲烷(10mL)和泊马度胺(1.6g，5.86mmol)，室温反应过夜，反应结束后，水萃取三次，收集有机相，有机相用饱和食盐水洗涤，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝120/1，v/v)纯化，得到白色固体化合物760mg，收率30.3％。
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),11.15(s,1H),9.70(s,1H),8.46(d,J＝8.4Hz,1H),7.83(t,J＝7.9Hz,1H),7.61(d,J＝7.3Hz,1H),5.14(dd,J＝12.8,5.4Hz,1H),2.66–2.52(m,2H),2.46(t,J＝7.5Hz,2H),2.20(t,J＝7.3Hz,2H),1.67–1.58(m,2H),1.53–1.46(m,2H),1.38–1.29(m,4H),1.28–1.17(m,2H).
(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)氨基甲酸酯叔丁酯的合成
称取化合物2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(500mg，1.81mmol)于25mL反应瓶中，加入DMF(5mL)溶解，向反应体系中加入(2-氨基乙基)氨基甲酸叔丁酯(18)(348mg，2.17mmol)和DIPEA(2mL)，90℃反应5h，TLC监测至原料反应完全，反应结束后，加入水淬灭，DCM萃取三次，有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝150/1，v/v)纯化，得到亮黄色固体化合物142mg，收率18.8％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.58(t,1H),7.14(d,J＝8.6Hz,1H),7.06–6.99(m,2H),6.72(t,J＝6.2Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.39–3.36(m,2H),3.11(q,2H),2.62–2.51(m,2H),2.10–1.90(m,2H),1.36(s,9H).
4-((2-氨基乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮的合成
将化合物(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)氨基甲酸酯叔丁酯(140mg，0.34mmol)溶于二氯甲烷(2mL)，缓慢滴加TFA(0.5mL)，室温反应2h，TLC监测至原料反应完全，反应结束后，减压浓缩除去溶剂，得到黄色油状液体104mg，收率98.1％。
5-溴-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)戊酰胺的合成
将4-((2-氨基乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(100mg，0.32mmol)溶于二氯甲烷(2mL)，加入5-溴戊酸(63mg，0.35mmol)、HATU(144mg，0.38mmol)和DIPEA(0.5mL)，室温反应5h，TLC监测至原料反应完全，反应结束后，水萃取三次，饱和食盐水洗涤有机层，经无水硫酸钠干燥，减压浓缩，经200-300目硅胶柱层析(DCM/MeOH＝60/1，v/v)纯化，得到黄色固体化合物85mg，收率56.1％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.06(t,J＝5.6Hz,1H),7.61–7.56(m,1H),7.18–7.16(m,1H),7.03(d,J＝7.0Hz,1H),6.72(t,J＝6.0Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.49(t,J＝6.6Hz,2H),3.27–3.22(m,2H),2.62–2.54(m,2H),2.11–2.06(m,2H),2.06–1.97(m,2H),1.77–1.73(m,2H),1.63–1.57(m,2H),1.29–1.25(m,2H).
6-叠氮-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺的合成
将化合物6-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺(200mg，0.44mmol)溶于四丁基氟化铵四氢呋喃溶液(2mL)，向反应体系中缓慢滴加叠氮基三甲基硅烷(1mL)，室温反应10h，反应结束后，减压浓缩除去溶剂，产物未经纯化直接进行下一步。
/>
2-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙酸叔丁酯的合成
将化合物8-环戊基-2-((4-(哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(50mg，0.13mmol)溶于乙腈(1mL)，加入溴乙酸叔丁酯(25mg，0.13mmol)和K2CO3(54mg，0.39mmol)，80℃回流5h，TLC监测至原料反应完全，反应结束后，加入适量的水淬灭，用EA萃取三次，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝150/1，v/v)纯化，得到黄色固体化合物35mg，收率54.2％。
1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.76(s,1H),7.83(s,1H),7.50(d,J＝8.7Hz,2H),6.93(d,J＝9.0Hz,2H),5.73–5.54(m,1H),3.15(s,2H),3.09(t,J＝5.0Hz,4H),2.64(t,J＝5.0Hz,4H),2.25–2.18(m,2H),1.97–1.84(m,2H),1.81–1.74(m,2H),1.61–1.55(m,2H),1.42(s,9H).
2-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙酸的合成
将化合物2-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙酸叔丁酯(30mg，0.06mmol)溶于二氯甲烷(2mL)，缓慢滴加TFA(0.5mL)，室温反应2h，TLC监测至原料反应完全，反应结束后，减压浓缩除去溶剂，得到黄色油状液体25mg，收率93.6％。
8-环戊基-2-((4-(4-(丙-2-炔-1-基)哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮的合成
将化合物8-环戊基-2-((4-(哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(50mg，0.13mmol)溶于DMF(1mL)，加入K2CO3(22mg，0.16mmol)、TBAB(4mg，0.01mmol)和3-溴丙炔(17mg，0.14mmol)，90℃反应3h，TLC监测至原料反应完全，反应结束后，水萃取三次，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝100/1，v/v)纯化，得到黄色固体化合物40mg，收率72.7％。
1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.76(s,1H),7.83(s,1H),7.51(d,J＝8.6Hz,2H),6.94(d,J＝9.0Hz,2H),5.70–5.57(m,1H),3.19(s,1H),3.12(t,J＝5.3Hz,4H),2.61(t,4H),2.26–2.18(m,2H),1.93–1.83(m,2H),1.82–1.75(m,2H),1.62–1.56(m,2H).
实施例3.目标化合物的合成
4-((2-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙氧基)氨基)-2-(2,6-二氧代哌啶-3)异吲哚啉-1,3-二酮(7a)的合成
称取化合物2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基4-甲基苯磺酸酯(70mg，0.14mmol)和8-环戊基-2-((4-(哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(50mg，0.13mmol)于25mL反应瓶中，加入DMF(2mL)溶解，向反应体系中缓慢滴加N,N-二异丙基乙胺(0.3mL)，升温至90℃反应4h，TLC监测至原料反应完全，反应完全后，加入适量的水萃取，有机相用饱和食盐水洗涤，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝35/1，v/v)纯化，得到黄色固体化合物13mg，收率13.4％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.95(s,1H),8.76(s,1H),7.83(s,1H),7.59(dd,J＝8.6,7.0Hz,1H),7.49(d,J＝8.6Hz,2H),7.16(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.89(d,J＝8.7Hz,2H),6.62(t,J＝5.8Hz,1H),5.73–5.52(m,1H),5.05(dd,J＝12.8,5.3Hz,1H),3.61(dt,J＝11.1,5.5Hz,4H),3.49(q,J＝5.5Hz,2H),3.04(t,J＝5.1Hz,4H),2.55(t,4H),2.27–2.17(m,2H),2.03–1.95(m,2H),1.92–1.82(m,2H),1.81–1.71(m,2H),1.63–1.52(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C38H42N10O6,734.3289；found735.3369.HPLC purity:98.65％,retention time＝1.450min.
4-((2-(2-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙氧基)乙氧基)氨基)-2-(2,6-二氧苯基-3-基)异吲哚啉-1,3-二酮(7b)的合成
合成步骤参照7a的合成，得到黄色固体，收率9.7％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.94(s,1H),8.76(s,1H),7.83(s,1H),7.58(dd,J＝8.6,7.1Hz,1H),7.49(d,J＝8.8Hz,2H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.90(d,J＝8.6Hz,2H),6.62(t,J＝5.8Hz,1H),5.73–5.53(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.64(t,J＝5.4Hz,2H),3.60–3.56(m,2H),3.56–3.51(m,4H),3.48(q,J＝5.4Hz,2H),3.08–2.99(m,4H),2.56–2.53(m,4H),2.26–2.18(m,2H),2.04–1.97(m,2H),1.93–1.81(m,2H),1.80–1.72(m,2H),1.62–1.52(m,2H).HRMS(ESI):(m/z):[M+H]+calcdfor C40H46N10O7,778.3551；found 779.3631.HPLC purity:98.94％,retention time＝1.490min.
6-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺(7c)的合成
称取化合物6-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺(15a)(91mg，0.20mmol)和8-环戊基-2-((4-(哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(6)(50mg，0.13mmol)于反应管中，加入乙腈(1mL)溶解，向反应体系中加入无水碳酸钾(89mg，0.64mmol)和碘化钾(20mg，0.12mmol)，80℃反应3h，TLC监测至原料反应完全，反应结束后，水萃取三次，饱和食盐水洗涤有机层，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝40/1，v/v)纯化，得到黄色固体化合物13mg，收率13.1％。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.94(s,1H),9.71(s,1H),8.76(s,1H),8.48(d,J＝8.4Hz,1H),7.95–7.75(m,2H),7.61(d,J＝7.2Hz,1H),7.50(d,J＝8.8Hz,2H),6.92(d,J＝9.0Hz,2H),5.65-5.60(m,1H),5.15(dd,J＝12.7,5.4Hz,1H),3.37(s,4H),3.09(s,4H),2.61-2.58(m,2H),2.35-2.30(m,2H),2.23-2.20(m,4H),2.01-1.98(m,2H),1.94–1.72(m,4H),1.70–1.64(m,2H),1.61–1.57(m,2H),1.53–1.45(m,2H),1.38-1.30(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C40H44N10O6,760.3445；found 761.3526.HPLCpurity:96.83％,retention time＝1.560min.
7-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚酰胺(7d)的合成
/>
合成步骤参照7c的合成，得到黄色固体化合物，收率10.5％。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.94(s,1H),9.69(s,1H),8.75(s,1H),8.47(d,J＝8.4Hz,1H),7.88–7.78(m,2H),7.60(d,J＝7.3Hz,1H),7.49(d,J＝8.5Hz,2H),6.91(d,J＝8.8Hz,2H),5.72–5.50(m,1H),5.15(dd,J＝12.8,5.4Hz,1H),3.34(t,4H),3.07(t,J＝4.7Hz,4H),2.67–2.52(m,2H),2.46–2.43(m,2H),2.30(t,J＝7.3Hz,2H),2.26–2.17(m,2H),2.11–1.94(m,2H),1.94–1.81(m,2H),1.80–1.71(m,2H),1.68–1.61(m,2H),1.60–1.53(m,2H),1.50–1.42(m,2H),1.38–1.30(m,4H).HRMS(ESI):(m/z):[M+H]+calcd forC41H46N10O6,774.3602；found 775.3685.HPLC purity:96.67％,retention time＝1.500min.
8-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)-8-氧代辛酰胺(7e)的合成
称取化合物8-环戊基-2-((4-(哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(30mg，0.08mmol)于反应管中，加入二氯甲烷溶解(1mL)，溶解之后向反应体系中加入EDCI(20mg，0.10mmol)、HOBT(15mg，0.11mmol)和8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-8-氧代辛酸(50mg，0.12mmol)，室温反应过夜，TLC监测至原料反应完全，反应结束后，水萃取三次，饱和食盐水洗涤有机层，经无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝100/1，v/v)纯化，得到黄色固体化合物11mg，收率17.6％。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.97(s,1H),9.70(s,1H),8.77(s,1H),8.47(d,J＝8.4Hz,1H),7.84(d,J＝1.8Hz,1H),7.81(d,J＝8.1Hz,1H),7.60(d,J＝7.3Hz,1H),7.53(d,J＝8.7Hz,2H),6.96(d,J＝9.0Hz,2H),5.73–5.47(m,1H),5.15(dd,J＝12.8,5.4Hz,1H),3.59(t,J＝5.4Hz,4H),3.14–2.99(m,4H),2.68–2.52(m,2H),2.48–2.44(m,2H),2.35(t,J＝7.4Hz,2H),2.28–2.18(m,2H),2.12–1.99(m,2H),1.89(d,J＝12.8Hz,2H),1.82–1.73(m,2H),1.67–1.57(m,4H),1.54–1.48(m,2H),1.36–1.32(m,4H).HRMS(ESI):(m/z):[M+H]+calcd for C42H46N10O7,802.3551；found 803.3625.HPLC purity:98.89％,retention time＝1.394min.
5-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-4-基)氨基)乙基)戊酰胺(7f)的合成
合成步骤参照7c的合成，得到黄色固体化合物，收率11.2％。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.94(s,1H),8.76(s,1H),8.04(t,J＝5.7Hz,1H),7.83(s,1H),7.59(dd,J＝8.6,7.1Hz,1H),7.50(d,J＝8.6Hz,2H),7.18(d,J＝8.7Hz,1H),7.03(d,J＝7.0Hz,1H),6.92(d,J＝8.8Hz,2H),6.73(t,J＝6.1Hz,1H),5.72–5.50(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.42–3.35(m,4H),3.31–3.21(m,4H),3.07(t,4H),2.61–2.53(m,2H),2.35–2.26(m,2H),2.25–2.16(m,2H),2.11–2.06(m,2H),2.05–1.95(m,2H),1.94–1.82(m,2H),1.81–1.71(m,2H),1.58(t,J＝5.8Hz,2H),1.51(q,J＝7.4Hz,2H),1.45–1.39(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C41H47N11O6,789.3711；found790.3786.HPLC purity:97.35％,retention time＝1.401min.
6-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)-N-(2-((2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-4-基)氨基)乙基)己酰胺(7g)的合成
合成步骤参照7c的合成，得到黄色固体化合物，收率12.4％。
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.95(s,1H),8.76(s,1H),8.07–8.00(m,1H),7.83(s,1H),7.58(t,J＝7.8Hz,1H),7.50(d,J＝8.5Hz,2H),7.17(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.92(d,J＝8.6Hz,2H),6.72(t,J＝6.2Hz,1H),5.71–5.53(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.25(t,J＝6.0Hz,4H),3.15–3.01(m,4H),2.64–2.52(m,4H),2.40–2.27(m,2H),2.25–2.17(m,2H),2.12–1.96(m,4H),1.95–1.81(m,2H),1.81–1.72(m,2H),1.57(q,J＝7.4,6.7Hz,2H),1.51(t,J＝7.4Hz,2H),1.46–1.39(m,2H),1.27–1.20(m,4H).HRMS(ESI):(m/z):[M+H]+calcd for C42H49N11O6,803.3867；found 804.3947.HPLCpurity:98.58％,retention time＝1.482min.
2-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁基)乙酰胺(7h)的合成
将化合物2-(4-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙酸(52mg，0.12mmol)溶于DMF(1mL)，加入4-((4-氨基丁基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(20mg，0.06mmol)、HATU(26mg，0.07mmol)和DIPEA(0.3mL)，室温反应5h，TLC监测至原料反应完全，反应结束后，加入水淬灭，用EA萃取，收集有机相，有机相经饱和食盐水洗涤，经无水硫酸钠干燥，产物经200-300目硅胶柱层析(DCM/MeOH＝50/1，v/v)纯化，得到黄色固体化合物10mg，收率22.2％。
1H NMR(600MHz,DMSO-d6)δ11.08(s,1H),9.95(s,1H),8.76(s,1H),7.83(s,2H),7.57(dd,J＝8.6,7.0Hz,1H),7.50(d,J＝8.5Hz,2H),7.11(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.91(d,J＝8.7Hz,2H),6.57(t,J＝6.1Hz,1H),5.72–5.51(m,1H),5.04(dd,J＝12.8,5.5Hz,1H),3.32–3.30(m,2H),3.17–3.14(m,2H),3.11(t,J＝5.3Hz,4H),2.96(s,2H),2.56(t,J＝4.9Hz,4H),2.53–2.51(m,2H),2.26–2.19(m,2H),2.04–1.95(m,2H),1.94–1.81(m,2H),1.80–1.73(m,2H),1.60–1.54(m,4H),1.53–1.48(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C40H45N11O6,775.3554；found 776.3636.HPLC purity:99.69％,retentiontime＝1.387min.
6-(4-((4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)甲基)-1H-1,2,3-三唑-1-基)-N-(2-(2,6-二氧苯基-3-基)-1,3-二氧异吲哚啉-4-基)六酰胺(7i)的合成
将化合物8-环戊基-2-((4-(4-(丙-2-炔-1-基)哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(30mg，0.07mmol)和6-叠氮-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺(35mg，0.08mmol)溶于叔丁醇/二氯甲烷(2/1，v/v)的混合溶液中(4mL)，加入抗坏血酸钠(42mg，0.21mmol)和硫酸铜水溶液(1mL)，室温反应10min，反应结束后，加入水淬灭，DCM萃取，无水硫酸钠干燥有机相，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝50/1，v/v)纯化，得到黄色固体化合物8mg，收率13.6％。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.94(s,1H),9.70(s,1H),8.75(s,1H),8.45(d,J＝8.4Hz,1H),8.03(s,1H),7.82(s,1H),7.80(d,J＝7.9Hz,1H),7.61(d,J＝7.3Hz,1H),7.49(d,J＝8.5Hz,2H),6.91(d,J＝8.6Hz,2H),5.72–5.51(m,1H),5.14(dd,J＝12.8,5.4Hz,1H),4.35(t,J＝7.1Hz,2H),3.62(s,2H),3.19–2.99(m,6H),2.60–2.53(m,4H),2.48–2.44(m,2H),2.22(t,J＝10.0Hz,2H),2.13–1.95(m,2H),1.87(q,J＝7.4Hz,4H),1.79–1.71(m,2H),1.65(t,J＝7.5Hz,2H),1.58–1.55(m,2H),1.32–1.30(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C43H47N13O6,841.3772；found 842.3853.HPLC purity:99.46％,retention time＝1.380min.
5-(4-((4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3)异吲哚啉-1,3-二酮(7j)的合成
将化合物8-环戊基-2-((4-(4-(哌啶-4-基甲基)哌嗪-1-基)苯基)氨基)蝶啶-7(8H)-酮(88mg，0.18mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(50mg，0.18mmol)溶于NMP(2mL)，加入DIPEA(0.3mL)，微波反应：150℃、30min、150PSI、50w。反应结束后，水萃取三次，有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩除去溶剂，产物经200-300目硅胶柱层析(DCM/MeOH＝25/1，v/v)纯化，得到黄色固体化合物8mg，收率5.9％。
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.95(s,1H),8.76(s,1H),7.83(s,1H),7.65(d,J＝8.5Hz,1H),7.50(d,J＝8.5Hz,2H),7.31(d,J＝2.2Hz,1H),7.22(dd,J＝8.8,2.3Hz,1H),6.93(d,J＝8.7Hz,2H),5.73–5.52(m,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.05(d,J＝12.8Hz,2H),3.10(t,4H),2.97(t,J＝12.7Hz,2H),2.63–2.53(m,2H),2.25–2.15(m,4H),2.06–1.96(m,2H),1.96–1.64(m,8H),1.64–1.55(m,2H),1.54–1.39(m,1H).HRMS(ESI):(m/z):[M+H]+calcd for C40H44N10O5,744.3496；found 745.3572.HPLC purity:95.47％,retention time＝1.946min.
5-(4-((1-(2-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧戊环-3-基)异吲哚啉-1,3-二酮(7k)的合成
合成步骤参照7h的合成，得到黄色固体化合物，收率8.7％。
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.95(s,1H),8.76(s,1H),7.83(s,1H),7.67(d,J＝8.5Hz,1H),7.51(d,J＝8.6Hz,2H),7.33(d,J＝2.3Hz,1H),7.24(dd,J＝8.8,2.3Hz,1H),6.94(d,J＝8.8Hz,2H),5.73–5.53(m,1H),5.07(dd,J＝12.9,5.4Hz,1H),3.69–3.54(m,2H),3.48–3.38(m,6H),3.17–3.08(m,6H),2.73(s,1H),2.63–2.53(m,6H),2.25–2.15(m,4H),2.00(dd,J＝10.5,5.0Hz,2H),1.92–1.71(m,8H),1.61–1.55(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C46H54N12O6,870.4289；found 871.4370.HPLC purity:99.27％,retention time＝1.461min.
5-(4-(2-(4-((8-环戊基-7-氧代-7,8-二氢蝶啶-2-基)氨基)苯基)哌嗪-1-基)乙酰基)哌嗪-1-基)-2-(2,6-二氧苯基)异吲哚啉-1,3-二酮(7l)的合成
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.95(s,1H),8.76(s,1H),7.83(s,1H),7.69(d,J＝8.5Hz,1H),7.50(d,J＝8.5Hz,2H),7.37(d,J＝2.2Hz,1H),7.26(dd,J＝8.7,2.3Hz,1H),6.94(d,J＝8.7Hz,2H),5.77–5.49(m,1H),5.07(dd,J＝13.0,5.3Hz,1H),3.74(d,J＝5.6Hz,2H),3.62(t,J＝5.9Hz,4H),3.50(t,4H),3.29(s,2H),3.12(t,4H),2.60(t,4H),2.28–2.15(m,2H),2.09–1.95(m,2H),1.95–1.81(m,2H),1.80–1.69(m,2H),1.63–1.50(m,2H).HRMS(ESI):(m/z):[M+H]+calcd for C40H43N11O6,773.3398；found 774.3481.HPLCpurity:99.63％,retention time＝1.381min.
实施例4、化合物对Jurkat细胞中的CDK各种亚型蛋白表达的影响
细胞株选用Jurkat细胞(该细胞株高表达CDK4/6蛋白)，在96孔板中，8000个细胞/孔，药物作用初始浓度10μM，三倍梯度稀释7次，药物终止浓度为4.15nM，共八个药物作用浓度。种板后加药作用72h，作用72h后，每孔加入10μL CCK8溶液，孵育3-4h后，酶标仪读取细胞的OD值。算出细胞的生存率。利用Graphpad拟合。图中可以看出化合物在1μM浓度下对CDK4/6表现出降解活性。化合物对CDK4/6蛋白的降解活性如表3和图1所示。
表3化合物7a-7l的DC50值和Dmax值
讨论：
发明人经过广泛而深入的研究，设计并合成得到了一系列未见文献报道的靶向CDK4/6的PROTAC分子，对合成的化合物进行了细胞水平降解活性测试，得到一批能够降解CDK4/6蛋白的化合物。为由CDK4/6介导的癌症的治疗奠定了基础。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.式(I)所示的化合物，或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
其中，R1选自下组：未取代的或取代的(优选卤素取代的)C1-C10直链或支链烷基、未取代的或取代的(优选卤素取代的)的C3-C8环烷基、未取代或取代的C3-C8杂环基、未取代或取代的C5-C10芳基、未取代或取代的C5-C10芳杂环基；
R2选自下组：氢、乙酰基、氰基、未取代或取代的C1-C10烷基、未取代或取代的C3-C8环烷基、未取代或取代的C3-C8杂环基、未取代或取代的C5-C10芳基、未取代或取代的C5-C10芳杂环基、未取代或取代的C1-C10烷基酰基、未取代或取代的酰胺基；
R3选自下组：C1-C8烷基或C1-C8氨基烷基取代的伯氨基或仲胺基、C3-C6环烷基取代的伯氨基、N上未取代或有C1-C6烷基取代的哌嗪基；
X为取代或未取代的CH或N；
Linker如下式所示：
m为0-12，优选1-8，更优选1-6，最优选1-3的整数；
n为0-6，优选1-4的整数；
Y为羰基或取代或未取代的CH2。
2.如权利要求1所述的化合物，或其异构体、药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述化合物是式(II)所示化合物：
其中，R1、R2、R3、X、Linker、m和n如权利要求1所述；
Y为羰基或取代或未取代的CH2。
3.根据权利要求2所述的化合物，其特征在于，R1选自未取代或取代的(优选卤素取代的)甲基、乙基、叔丁基、异丙基或环戊烷基、或未取代的或在杂原子上有C1-C6取代基的C3-C8杂环基。
4.根据权利要求1所述的化合物，其特征在于，R2为乙酰基、取代或未取代的C5-C10芳杂环基，取代或未取代的酰胺基；
X为CH或N。
5.根据权利要求1所述的化合物，其特征在于，R3为C1-C8烷基取代的仲胺基或者N上未取代的或有C1-C3烷基取代的哌嗪基。
6.选自下组的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
7.根据权利要求1所述的化合物，其特征在于，R1是未取代的或取代的(优选卤素取代的)的C3-C8环烷基(优选C4-C6环烷基)；
R2是氢；
R3是N上未取代或有C1-C6烷基取代的哌嗪基；
X为取代或未取代的CH；
Linker如下式所示：
m为1-3的整数；
n为1-4的整数；
Y为羰基。
8.选自下组的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药：
9.一种药物组合物，其特征在于，含有权利要求1-8任一所述的化合物或其异构体、药学上可接受的盐、水合物、溶剂化物或前药，以及药学上可接受的载体或赋形剂。
10.根据上述权利要求中任一项所述的化合物、或其异构体、药学上可接受的盐、水合物、溶剂化物或前药在制备治疗CDK蛋白激酶介导的疾病的药物或在制备食品或保健品中的用途。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210788227.1A CN117384161A (zh) | 2022-07-04 | 2022-07-04 | 靶向降解cdk蛋白的化合物及其应用 |
| PCT/CN2023/105759 WO2024008097A1 (zh) | 2022-07-04 | 2023-07-04 | 靶向降解cdk蛋白的化合物及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210788227.1A CN117384161A (zh) | 2022-07-04 | 2022-07-04 | 靶向降解cdk蛋白的化合物及其应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117384161A true CN117384161A (zh) | 2024-01-12 |
Family
ID=89454427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210788227.1A Pending CN117384161A (zh) | 2022-07-04 | 2022-07-04 | 靶向降解cdk蛋白的化合物及其应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN117384161A (zh) |
| WO (1) | WO2024008097A1 (zh) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008511B (zh) * | 2012-05-14 | 2018-08-14 | 华东理工大学 | 蝶啶酮衍生物及其作为egfr、blk、flt3抑制剂的应用 |
| CN110357885A (zh) * | 2019-07-24 | 2019-10-22 | 江南大学 | 一种蝶啶类化合物及其在药学上的应用 |
| WO2021083949A1 (en) * | 2019-10-29 | 2021-05-06 | F. Hoffmann-La Roche Ag | Bifunctional compounds for the treatment of cancer |
| MX2022006672A (es) * | 2019-12-04 | 2022-08-08 | Nurix Therapeutics Inc | Compuestos bifuncionales para la degradacion de btk a traves de la via de proteosomas de ubiquitina. |
| CN111892578B (zh) * | 2020-08-03 | 2023-10-20 | 沈阳药科大学 | 一种靶向降解黏着斑激酶的化合物及应用 |
| WO2022068933A1 (en) * | 2020-09-30 | 2022-04-07 | Cullgen (Shanghai) , Inc. | Compounds and methods of treating diseases |
| WO2022068849A1 (en) * | 2020-09-30 | 2022-04-07 | Beigene, Ltd. | Bifunctional compounds for degradation of egfr and related methods of use |
-
2022
- 2022-07-04 CN CN202210788227.1A patent/CN117384161A/zh active Pending
-
2023
- 2023-07-04 WO PCT/CN2023/105759 patent/WO2024008097A1/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024008097A1 (zh) | 2024-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7373992B2 (ja) | 過剰増殖性疾患の治療のための置換ピラゾール化合物およびそれらの使用方法 | |
| JP6114820B2 (ja) | プテリジノン誘導体およびｅｇｆｒ、ｂｌｋ、ｆｌｔ３の阻害剤としての応用 | |
| CA2903463A1 (en) | Bet bromodomain inhibitors and therapeutic methods using the same | |
| WO2010072166A1 (zh) | 二氢化茚酰胺化合物制备方法、包含其的药物组合物、及其作为蛋白激酶抑制剂的应用 | |
| CN106661025B (zh) | 一种周期素依赖性蛋白激酶抑制剂的羟乙基磺酸盐、其结晶形式及制备方法 | |
| CN116390728B (zh) | 喹唑啉衍生物及其制备方法和用途 | |
| KR20190098266A (ko) | 치환된 축합 헤테로아릴기 화합물인 키나제 억제제 및 이의 응용 | |
| CN112867717B (zh) | 用作激酶抑制剂的化合物及其应用 | |
| CN113518779B (zh) | 噻吩并杂环类衍生物、其制备方法及其在医药上的应用 | |
| WO2023078451A1 (zh) | 用作cdk7激酶抑制剂的化合物及其应用 | |
| WO2010096395A1 (en) | Amides as kinase inhibitors | |
| JP2018135268A (ja) | 新規ヘテロアリールアミノ−３−ピラゾール誘導体およびその薬理学上許容される塩 | |
| WO2017144025A1 (zh) | 作为EGFR抑制剂的嘧啶并[4,5-d][1,3]噁嗪-2-酮衍生物及其应用 | |
| Dai et al. | Design, synthesis and biological evaluation of 4-(4-aminophenoxy) picolinamide derivatives as potential antitumor agents | |
| US8258168B2 (en) | 2H or 3H-benzo[E]indazol-1-YL carbamate derivatives, the preparation and therapeutic use thereof | |
| CN106467540B (zh) | 蝶啶酮衍生物作为flt3抑制剂的应用 | |
| WO2017101862A1 (zh) | 作为egfr抑制剂的5,8-二氢蝶啶-6,7-二酮衍生物及其应用 | |
| CN117043163A (zh) | 吡咯并嘧啶类或吡咯并吡啶类衍生物及其医药用途 | |
| CN117384161A (zh) | 靶向降解cdk蛋白的化合物及其应用 | |
| CN111484495B (zh) | 含二氢蝶啶二酮骨架衍生物的制备方法和用途 | |
| CN109438279B (zh) | 一种克服egfr耐药突变的小分子化合物及其制备方法和用途 | |
| CN111732597A (zh) | 含4-酰胺苯氧基的2-氨基嘧啶杂环类化合物的制备及应用 | |
| CA3143813A1 (en) | Cdk kinase inhibitor | |
| CN113891749A (zh) | 喹啉衍生物及其用于治疗癌症的用途 | |
| JP2009073743A (ja) | 新規な縮合環式ピリミジン化合物又はその塩、及びその医薬組成物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |