JP2018507877A - CDK阻害剤としてのピラゾロ[1,5−a][1,3,5]トリアジンとピラゾロ[1,5−a]ピリミジン誘導体 - Google Patents
CDK阻害剤としてのピラゾロ[1,5−a][1,3,5]トリアジンとピラゾロ[1,5−a]ピリミジン誘導体 Download PDFInfo
- Publication number
- JP2018507877A JP2018507877A JP2017546949A JP2017546949A JP2018507877A JP 2018507877 A JP2018507877 A JP 2018507877A JP 2017546949 A JP2017546949 A JP 2017546949A JP 2017546949 A JP2017546949 A JP 2017546949A JP 2018507877 A JP2018507877 A JP 2018507877A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- amino
- pyrazolo
- mmol
- formula
- 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.)
- Granted
Links
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title abstract description 23
- JUXWUYWPUDKPSD-UHFFFAOYSA-N pyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=CN=CN2N=CC=C21 JUXWUYWPUDKPSD-UHFFFAOYSA-N 0.000 title abstract description 8
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 326
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 claims abstract description 63
- 108091007914 CDKs Proteins 0.000 claims abstract description 46
- 238000013518 transcription Methods 0.000 claims abstract description 42
- 230000035897 transcription Effects 0.000 claims abstract description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims abstract description 23
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims abstract description 23
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 claims abstract description 22
- 102100038114 Cyclin-dependent kinase 13 Human genes 0.000 claims abstract description 22
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 claims abstract description 22
- 101000884348 Homo sapiens Cyclin-dependent kinase 13 Proteins 0.000 claims abstract description 22
- 102100033144 Cyclin-dependent kinase 18 Human genes 0.000 claims abstract description 20
- 108010039798 PCTAIRE-3 protein kinase Proteins 0.000 claims abstract description 20
- 230000002103 transcriptional effect Effects 0.000 claims abstract description 14
- 208000035475 disorder Diseases 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 claims abstract 4
- -1 alkoxyalkoxyl Chemical group 0.000 claims description 162
- 238000000034 method Methods 0.000 claims description 136
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 117
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 206010028980 Neoplasm Diseases 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 210000004027 cell Anatomy 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 230000002159 abnormal effect Effects 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 230000001028 anti-proliverative effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 201000005787 hematologic cancer Diseases 0.000 claims description 3
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000010208 Seminoma Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 208000007538 neurilemmoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 201000005528 peripheral nervous system neoplasm Diseases 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 claims description 2
- 208000011594 Autoinflammatory disease Diseases 0.000 claims 1
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 206010039491 Sarcoma Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
- 201000007455 central nervous system cancer Diseases 0.000 claims 1
- 208000025997 central nervous system neoplasm Diseases 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 201000005228 cornea cancer Diseases 0.000 claims 1
- 208000024726 cornea neoplasm Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- 230000003325 follicular Effects 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 210000004324 lymphatic system Anatomy 0.000 claims 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 claims 1
- 201000010106 skin squamous cell carcinoma Diseases 0.000 claims 1
- 208000001608 teratocarcinoma Diseases 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 23
- 239000003112 inhibitor Substances 0.000 abstract description 14
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 262
- 238000003786 synthesis reaction Methods 0.000 description 161
- 230000015572 biosynthetic process Effects 0.000 description 156
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 150
- 239000011541 reaction mixture Substances 0.000 description 143
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 130
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 92
- 235000019439 ethyl acetate Nutrition 0.000 description 88
- 239000000243 solution Substances 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 67
- 238000006243 chemical reaction Methods 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- 101710106276 Cyclin-dependent kinase 7 Proteins 0.000 description 59
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 58
- 239000012267 brine Substances 0.000 description 58
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 58
- 239000012044 organic layer Substances 0.000 description 57
- 239000011734 sodium Substances 0.000 description 57
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 47
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
- 239000010410 layer Substances 0.000 description 43
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 42
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 42
- 239000003153 chemical reaction reagent Substances 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- 239000005457 ice water Substances 0.000 description 29
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 28
- 238000002953 preparative HPLC Methods 0.000 description 27
- 239000000376 reactant Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 19
- 239000007821 HATU Substances 0.000 description 18
- 108091000080 Phosphotransferase Proteins 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 17
- 102000020233 phosphotransferase Human genes 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 14
- 230000022131 cell cycle Effects 0.000 description 13
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 12
- ONPGOSVDVDPBCY-CQSZACIVSA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ONPGOSVDVDPBCY-CQSZACIVSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- ODUIXUGXPFKQLG-QWRGUYRKSA-N [2-(4-chloro-2-fluoroanilino)-5-methyl-1,3-thiazol-4-yl]-[(2s,3s)-2,3-dimethylpiperidin-1-yl]methanone Chemical compound C[C@H]1[C@@H](C)CCCN1C(=O)C1=C(C)SC(NC=2C(=CC(Cl)=CC=2)F)=N1 ODUIXUGXPFKQLG-QWRGUYRKSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 230000026731 phosphorylation Effects 0.000 description 10
- 238000006366 phosphorylation reaction Methods 0.000 description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
- 208000037765 diseases and disorders Diseases 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229940124531 pharmaceutical excipient Drugs 0.000 description 8
- IQHXABCGSFAKPN-UHFFFAOYSA-N pyrrolidine-3-carboxamide Chemical compound NC(=O)C1CCNC1 IQHXABCGSFAKPN-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229910052725 zinc Inorganic materials 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 102000009572 RNA Polymerase II Human genes 0.000 description 7
- 108010009460 RNA Polymerase II Proteins 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- KKCWBKUOPJMUQV-UHFFFAOYSA-N azetidine-2-carboxamide Chemical compound NC(=O)C1CCN1 KKCWBKUOPJMUQV-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000006369 cell cycle progression Effects 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 230000002062 proliferating effect Effects 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 5
- 102100036883 Cyclin-H Human genes 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000006196 drop Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000011534 wash buffer Substances 0.000 description 5
- DILISPNYIVRDBP-UHFFFAOYSA-N 2-[3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile Chemical compound OC(CNC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=CC2=CC=CC=C2C=C1)C DILISPNYIVRDBP-UHFFFAOYSA-N 0.000 description 4
- FQKJLOIDFLIVBZ-UHFFFAOYSA-N 4-N-[(3-aminophenyl)methyl]-2-N-(oxan-4-yl)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC(N)=CC=C3)N2N=C1 FQKJLOIDFLIVBZ-UHFFFAOYSA-N 0.000 description 4
- RRBPEHJNXHJYQN-UHFFFAOYSA-N 4-chloro-2-methylsulfanyl-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=C(SC)N=C(Cl)N2N=CC(C(C)C)=C21 RRBPEHJNXHJYQN-UHFFFAOYSA-N 0.000 description 4
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 101100533230 Caenorhabditis elegans ser-2 gene Proteins 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 108010068237 Cyclin H Proteins 0.000 description 4
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 4
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 4
- 101710177611 DNA polymerase II large subunit Proteins 0.000 description 4
- 101710184669 DNA polymerase II small subunit Proteins 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 4
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 4
- 229950010817 alvocidib Drugs 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 230000006806 disease prevention Effects 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- DMDVSBSKDHLQSH-UHFFFAOYSA-N phenyl 4-prop-2-enoylpiperazine-1-carboxylate Chemical compound C1(=CC=CC=C1)OC(=O)N1CCN(CC1)C(C=C)=O DMDVSBSKDHLQSH-UHFFFAOYSA-N 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- DOTGZROJTAUYFQ-OWOJBTEDSA-N (e)-4-bromobut-2-enoic acid Chemical compound OC(=O)\C=C\CBr DOTGZROJTAUYFQ-OWOJBTEDSA-N 0.000 description 3
- WYYZMOWBDJCGSN-UHFFFAOYSA-N 4-chloro-8-ethyl-2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazine Chemical compound ClC1=NC(SC)=NC2=C(CC)C=NN21 WYYZMOWBDJCGSN-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- FYJRPGYVRHJSPJ-UHFFFAOYSA-N C(C)(C)C=1C=NN2C1N=C(N=C2)OC2CCN(CC2)C Chemical compound C(C)(C)C=1C=NN2C1N=C(N=C2)OC2CCN(CC2)C FYJRPGYVRHJSPJ-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 102100040428 Chitobiosyldiphosphodolichol beta-mannosyltransferase Human genes 0.000 description 3
- 102000016736 Cyclin Human genes 0.000 description 3
- 108050006400 Cyclin Proteins 0.000 description 3
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 3
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 3
- 230000033616 DNA repair Effects 0.000 description 3
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 101000891557 Homo sapiens Chitobiosyldiphosphodolichol beta-mannosyltransferase Proteins 0.000 description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- YBXBWBBVLXZQBJ-UHFFFAOYSA-N n-[2-(5-hydroxy-2-methyl-1h-indol-3-yl)ethyl]-2-methoxyacetamide Chemical compound C1=C(O)C=C2C(CCNC(=O)COC)=C(C)NC2=C1 YBXBWBBVLXZQBJ-UHFFFAOYSA-N 0.000 description 3
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 3
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 3
- XIMBESZRBTVIOD-UHFFFAOYSA-N piperidine-2-carboxamide Chemical compound NC(=O)C1CCCCN1 XIMBESZRBTVIOD-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 2
- UUHNQHFOIVLAQX-BJILWQEISA-N (e)-4-(dimethylamino)but-2-enoic acid;hydrochloride Chemical compound Cl.CN(C)C\C=C\C(O)=O UUHNQHFOIVLAQX-BJILWQEISA-N 0.000 description 2
- ITGIYLMMAABTHC-ONEGZZNKSA-N (e)-4-(dimethylazaniumyl)but-2-enoate Chemical compound CN(C)C\C=C\C(O)=O ITGIYLMMAABTHC-ONEGZZNKSA-N 0.000 description 2
- NQQRXZOPZBKCNF-NSCUHMNNSA-N (e)-but-2-enamide Chemical compound C\C=C\C(N)=O NQQRXZOPZBKCNF-NSCUHMNNSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- KDKGWGUUUVROTO-UHFFFAOYSA-N 1-hydroxypiperazine Chemical compound ON1CCNCC1 KDKGWGUUUVROTO-UHFFFAOYSA-N 0.000 description 2
- BAUWRHPMUVYFOD-UHFFFAOYSA-N 1-methylpiperidin-4-ol Chemical compound CN1CCC(O)CC1 BAUWRHPMUVYFOD-UHFFFAOYSA-N 0.000 description 2
- XBUIBIHOIQNJQG-UHFFFAOYSA-N 1-prop-2-enoylpiperidine-4-carboxylic acid Chemical compound OC(=O)C1CCN(C(=O)C=C)CC1 XBUIBIHOIQNJQG-UHFFFAOYSA-N 0.000 description 2
- OFAPSLLQSSHRSQ-UHFFFAOYSA-N 1H-triazine-2,4-diamine Chemical compound NN1NC=CC(N)=N1 OFAPSLLQSSHRSQ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- SSORSZACHCNXSJ-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NCC(C)O SSORSZACHCNXSJ-UHFFFAOYSA-N 0.000 description 2
- ZPHHKTYSYNNWND-UHFFFAOYSA-N 2-methoxy-N-[(3-nitrophenyl)methyl]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound COC1=NC2=C(C=NN2C(NCC2=CC(=CC=C2)[N+]([O-])=O)=N1)C(C)C ZPHHKTYSYNNWND-UHFFFAOYSA-N 0.000 description 2
- FHSGTJQXDKTDAV-UHFFFAOYSA-N 2-methylsulfonyl-N-[(3-nitrophenyl)methyl]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound CC(C)C1=C2N=C(N=C(NCC3=CC(=CC=C3)[N+]([O-])=O)N2N=C1)S(C)(=O)=O FHSGTJQXDKTDAV-UHFFFAOYSA-N 0.000 description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- MFABFKUNLDYKGH-UHFFFAOYSA-N 3-cyclohexyl-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1H-pyrimidine-2,4-dione Chemical group FC(F)(F)C1=CC=CC(N2CCN(CC2)C=2NC(=O)N(C3CCCCC3)C(=O)C=2)=C1 MFABFKUNLDYKGH-UHFFFAOYSA-N 0.000 description 2
- BTIDYJKZPLRVTG-UHFFFAOYSA-N 3-fluoro-1-methyl-4-phenylmethoxypiperidine Chemical compound C(C1=CC=CC=C1)OC1C(CN(CC1)C)F BTIDYJKZPLRVTG-UHFFFAOYSA-N 0.000 description 2
- HYJMPMKNCACNOC-UHFFFAOYSA-N 3-fluoro-1-methylpiperidin-4-ol Chemical compound CN1CCC(O)C(F)C1 HYJMPMKNCACNOC-UHFFFAOYSA-N 0.000 description 2
- AVXCVBXAVNDIGV-UHFFFAOYSA-N 3-fluoro-4-phenylmethoxypiperidine Chemical compound C(C1=CC=CC=C1)OC1C(CNCC1)F AVXCVBXAVNDIGV-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- LWTPSGRKBRPXOJ-UHFFFAOYSA-N 5-chloro-N-[(3-nitrophenyl)methyl]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-amine Chemical compound ClC1=NC=2N(C(=C1)NCC1=CC(=CC=C1)[N+](=O)[O-])N=CC=2C(C)C LWTPSGRKBRPXOJ-UHFFFAOYSA-N 0.000 description 2
- FZLSDZZNPXXBBB-KDURUIRLSA-N 5-chloro-N-[3-cyclopropyl-5-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]phenyl]-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine Chemical compound C[C@H]1CN(Cc2cc(Nc3ncc(Cl)c(n3)-c3c[nH]c4cc(C)ccc34)cc(c2)C2CC2)C[C@@H](C)N1 FZLSDZZNPXXBBB-KDURUIRLSA-N 0.000 description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- BWJHJLINOYAPEG-HOTGVXAUSA-N 8-chloro-6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclopentyl]-7-methyl-2H-1,3-benzoxazin-4-one Chemical compound ClC1=C(C(=CC=2C(N(COC=21)[C@@H]1[C@H](CCC1)O)=O)CC=1C=NC(=CC=1)Cl)C BWJHJLINOYAPEG-HOTGVXAUSA-N 0.000 description 2
- VOISLPCWNIKHOB-UHFFFAOYSA-N 8-ethyl-2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Chemical compound CCC1=C2N=C(NC(=O)N2N=C1)SC VOISLPCWNIKHOB-UHFFFAOYSA-N 0.000 description 2
- XJWRMWPYNPZZHO-UHFFFAOYSA-N 8-ethyl-2-methylsulfonyl-N-[(3-nitrophenyl)methyl]pyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound CCC1=C2N=C(N=C(NCC3=CC(=CC=C3)[N+]([O-])=O)N2N=C1)S(C)(=O)=O XJWRMWPYNPZZHO-UHFFFAOYSA-N 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- YYOYSDSTPRROMW-UHFFFAOYSA-N C(C)(C)(C)N(C(O)=O)C1=CC(=C(C=C1)Br)C#N Chemical compound C(C)(C)(C)N(C(O)=O)C1=CC(=C(C=C1)Br)C#N YYOYSDSTPRROMW-UHFFFAOYSA-N 0.000 description 2
- VQCOUJMZNYCUNT-UHFFFAOYSA-N C(C)(C)(C)N(C(O)=O)C1=CC(=C(C=C1)CC)C#N Chemical compound C(C)(C)(C)N(C(O)=O)C1=CC(=C(C=C1)CC)C#N VQCOUJMZNYCUNT-UHFFFAOYSA-N 0.000 description 2
- GEUSTEUHZVGSMO-UHFFFAOYSA-N C(C)(C)(C)N(C(O)=O)C1=CC(=C(C=C1)CC)CN Chemical compound C(C)(C)(C)N(C(O)=O)C1=CC(=C(C=C1)CC)CN GEUSTEUHZVGSMO-UHFFFAOYSA-N 0.000 description 2
- FHAIDUKTSDDUIN-UHFFFAOYSA-N CCC1=C2NC(=S)NC(=O)N2N=C1 Chemical compound CCC1=C2NC(=S)NC(=O)N2N=C1 FHAIDUKTSDDUIN-UHFFFAOYSA-N 0.000 description 2
- 102100030933 CDK-activating kinase assembly factor MAT1 Human genes 0.000 description 2
- 229940125888 CDK7 inhibitor Drugs 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 108010068106 Cyclin T Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 102100036876 Cyclin-K Human genes 0.000 description 2
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- LRULVYSBRWUVGR-FCHUYYIVSA-N GSK2879552 Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCC(CN[C@H]2[C@@H](C2)C=2C=CC=CC=2)CC1 LRULVYSBRWUVGR-FCHUYYIVSA-N 0.000 description 2
- 101000583935 Homo sapiens CDK-activating kinase assembly factor MAT1 Proteins 0.000 description 2
- 101000713127 Homo sapiens Cyclin-K Proteins 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- ZTCLCSCHTACERP-AWEZNQCLSA-N N-[(1S)-1-[3-chloro-5-fluoro-2-[[2-methyl-4-(2-methyl-1,2,4-triazol-3-yl)quinolin-8-yl]oxymethyl]phenyl]ethyl]-2-(difluoromethoxy)acetamide Chemical compound C1=C(C=C(C(=C1Cl)COC1=CC=CC2=C(C=3N(N=CN=3)C)C=C(C)N=C12)[C@@H](NC(=O)COC(F)F)C)F ZTCLCSCHTACERP-AWEZNQCLSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 2
- 159000000021 acetate salts Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 108010089576 carboxy-terminal domain kinase Proteins 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 108091006104 gene-regulatory proteins Proteins 0.000 description 2
- 102000034356 gene-regulatory proteins Human genes 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- YLASUYCRADETMX-UHFFFAOYSA-N n-(3-aminophenyl)-4-nitrobenzamide Chemical compound NC1=CC=CC(NC(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=C1 YLASUYCRADETMX-UHFFFAOYSA-N 0.000 description 2
- OBJNFLYHUXWUPF-IZZDOVSWSA-N n-[3-[[5-chloro-4-(1h-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(e)-4-(dimethylamino)but-2-enoyl]amino]benzamide Chemical compound C1=CC(NC(=O)/C=C/CN(C)C)=CC=C1C(=O)NC1=CC=CC(NC=2N=C(C(Cl)=CN=2)C=2C3=CC=CC=C3NC=2)=C1 OBJNFLYHUXWUPF-IZZDOVSWSA-N 0.000 description 2
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 2
- NENLIGJPMYKXNE-UHFFFAOYSA-N phenyl piperazine-1-carboxylate Chemical compound C1CNCCN1C(=O)OC1=CC=CC=C1 NENLIGJPMYKXNE-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- KOXPDOIQJWADCD-UHFFFAOYSA-N tert-butyl 3-[(3-acetylphenyl)carbamoyl]piperidine-1-carboxylate Chemical compound CC(=O)C1=CC=CC(NC(=O)C2CN(CCC2)C(=O)OC(C)(C)C)=C1 KOXPDOIQJWADCD-UHFFFAOYSA-N 0.000 description 2
- COKUVWKVGQDWSW-UHFFFAOYSA-N tert-butyl 3-[(5-cyano-2-fluorophenyl)carbamoyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C1)C(=O)NC1=C(F)C=CC(=C1)C#N COKUVWKVGQDWSW-UHFFFAOYSA-N 0.000 description 2
- GKTFJMUSQMYVMI-UHFFFAOYSA-N tert-butyl 3-[[3-(1-aminoethyl)phenyl]carbamoyl]piperidine-1-carboxylate Chemical compound NC(C)C=1C=C(C=CC=1)NC(=O)C1CN(CCC1)C(=O)OC(C)(C)C GKTFJMUSQMYVMI-UHFFFAOYSA-N 0.000 description 2
- AXUZABJEWVCPNX-UHFFFAOYSA-N tert-butyl 3-[[5-(aminomethyl)-2-fluorophenyl]carbamoyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C1)C(=O)NC1=C(F)C=CC(CN)=C1 AXUZABJEWVCPNX-UHFFFAOYSA-N 0.000 description 2
- XRNLYXKYODGLMI-UHFFFAOYSA-N tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C(F)C1 XRNLYXKYODGLMI-UHFFFAOYSA-N 0.000 description 2
- ABPXAMVUXVELLR-UHFFFAOYSA-N tert-butyl 3-fluoro-4-phenylmethoxypiperidine-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC1C(CN(CC1)C(=O)OC(C)(C)C)F ABPXAMVUXVELLR-UHFFFAOYSA-N 0.000 description 2
- XVUGYASNBHHQBN-UHFFFAOYSA-N tert-butyl 4-[(3-nitrobenzoyl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC(=O)C1=CC=CC([N+]([O-])=O)=C1 XVUGYASNBHHQBN-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- CIUYJYRQKYGNQP-UHFFFAOYSA-N (3-nitrophenyl)methanamine Chemical compound NCC1=CC=CC([N+]([O-])=O)=C1 CIUYJYRQKYGNQP-UHFFFAOYSA-N 0.000 description 1
- PMKIOIVNPIBRSE-UHFFFAOYSA-N (3-nitrophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=CC([N+]([O-])=O)=C1 PMKIOIVNPIBRSE-UHFFFAOYSA-N 0.000 description 1
- DNBCBAXDWNDRNO-FOSCPWQOSA-N (3aS,6aR)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide Chemical compound COC1=NSC(NC(=O)N2C[C@H]3CC(C[C@H]3C2)N(C)C=2C=3C=CNC=3N=CN=2)=N1 DNBCBAXDWNDRNO-FOSCPWQOSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- OIIOPWHTJZYKIL-PMACEKPBSA-N (5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one Chemical compound C1(=C(N=C(C2=C(C(C3=CC=CC(=C3Cl)C3=NC(OC)=C(N=C3)CNC[C@H]3NC(=O)CC3)=CC=C2)Cl)C=N1)OC)CNC[C@H]1NC(=O)CC1 OIIOPWHTJZYKIL-PMACEKPBSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- ZMKNIPLPPQUZPM-ONEGZZNKSA-N (E)-4-bromo-1-[4-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]piperidin-1-yl]but-2-en-1-one Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3CCN(CC3)C(=O)\C=C\CBr)N2N=C1 ZMKNIPLPPQUZPM-ONEGZZNKSA-N 0.000 description 1
- ACFFAMJSFZINGL-OWOJBTEDSA-N (e)-4-bromobut-2-enoyl chloride Chemical compound ClC(=O)\C=C\CBr ACFFAMJSFZINGL-OWOJBTEDSA-N 0.000 description 1
- YKIKDQYYTAOTPL-IHWYPQMZSA-N (z)-2-bromobut-2-enoic acid Chemical compound C\C=C(/Br)C(O)=O YKIKDQYYTAOTPL-IHWYPQMZSA-N 0.000 description 1
- KCZIUKYAJJEIQG-UHFFFAOYSA-N 1,3,5-triazin-2-amine Chemical compound NC1=NC=NC=N1 KCZIUKYAJJEIQG-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- WZCQRUWWHSTZEM-UHFFFAOYSA-N 1,3-phenylenediamine Chemical compound NC1=CC=CC(N)=C1 WZCQRUWWHSTZEM-UHFFFAOYSA-N 0.000 description 1
- JQAOHGMPAAWWQO-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCCC1C(O)=O JQAOHGMPAAWWQO-UHFFFAOYSA-N 0.000 description 1
- NXILIHONWRXHFA-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC(C(O)=O)C1 NXILIHONWRXHFA-UHFFFAOYSA-N 0.000 description 1
- HRMRQBJUFWFQLX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)C1 HRMRQBJUFWFQLX-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- OMMBYRSUPXNTEK-UHFFFAOYSA-N 1-methyl-4-nitro-1h-pyrazole-3-carboxylic acid Chemical compound CN1C=C([N+]([O-])=O)C(C(O)=O)=N1 OMMBYRSUPXNTEK-UHFFFAOYSA-N 0.000 description 1
- CHTXGINJDXVDJE-UHFFFAOYSA-N 1-methyl-4-nitro-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]pyrazole-3-carboxamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(=O)C1=NN(C=C1[N+](=O)[O-])C)NC1CCOCC1 CHTXGINJDXVDJE-UHFFFAOYSA-N 0.000 description 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 1
- URBHUGQFAFSSRQ-UHFFFAOYSA-N 1-prop-2-enoylpiperidine-3-carboxamide Chemical compound NC(=O)C1CCCN(C(=O)C=C)C1 URBHUGQFAFSSRQ-UHFFFAOYSA-N 0.000 description 1
- VBROFLVSVXVQEG-UHFFFAOYSA-N 1-prop-2-enoylpiperidine-3-carboxylic acid Chemical compound OC(=O)C1CCCN(C(=O)C=C)C1 VBROFLVSVXVQEG-UHFFFAOYSA-N 0.000 description 1
- WQPSGGYLCOXBKT-UHFFFAOYSA-N 1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound NC(=O)C1CCN(C1)C(=O)C=C WQPSGGYLCOXBKT-UHFFFAOYSA-N 0.000 description 1
- WAQCGNDULBMNQJ-UHFFFAOYSA-N 1-prop-2-enoylpyrrolidine-3-carboxylic acid Chemical compound OC(=O)C1CCN(C(=O)C=C)C1 WAQCGNDULBMNQJ-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical class C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- BKPCRRJDURRPGO-UHFFFAOYSA-N 2-N-(oxan-4-yl)-4-N-(piperidin-4-ylmethyl)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3CCNCC3)N2N=C1 BKPCRRJDURRPGO-UHFFFAOYSA-N 0.000 description 1
- LIBDITWYYOVSRX-UHFFFAOYSA-N 2-N-(oxan-4-yl)-4-N-[(2-piperazin-1-ylphenyl)methyl]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC1=C(C=CC=C1)N1CCNCC1)NC1CCOCC1 LIBDITWYYOVSRX-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- KDDPNNXAZURUGP-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1 KDDPNNXAZURUGP-UHFFFAOYSA-N 0.000 description 1
- BWSQKOKULIALEW-UHFFFAOYSA-N 2-[2-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound FC1=C(C=C(C=C1)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1)C(F)(F)F BWSQKOKULIALEW-UHFFFAOYSA-N 0.000 description 1
- LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- DOBWRWWGRZTEHG-UHFFFAOYSA-N 2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Chemical compound O=C1NC(SC)=NC2=CC=NN21 DOBWRWWGRZTEHG-UHFFFAOYSA-N 0.000 description 1
- RCKVVBITDJOWER-UHFFFAOYSA-N 2-methylsulfanyl-N-(3-nitrophenyl)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NC1=CC(=CC=C1)[N+](=O)[O-])SC RCKVVBITDJOWER-UHFFFAOYSA-N 0.000 description 1
- BMMOQPOBIICKAU-UHFFFAOYSA-N 2-methylsulfanyl-N-[(3-nitrophenyl)methyl]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound CSC1=NC2=C(C=NN2C(NCC2=CC(=CC=C2)[N+]([O-])=O)=N1)C(C)C BMMOQPOBIICKAU-UHFFFAOYSA-N 0.000 description 1
- IYJYWSZUXVSRIE-UHFFFAOYSA-N 2-methylsulfonyl-N-(3-nitrophenyl)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NC1=CC(=CC=C1)[N+](=O)[O-])S(=O)(=O)C IYJYWSZUXVSRIE-UHFFFAOYSA-N 0.000 description 1
- YUCHBNPEXIKPHN-UHFFFAOYSA-N 2h-pyran-4-amine Chemical compound NC1=CCOC=C1 YUCHBNPEXIKPHN-UHFFFAOYSA-N 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
- BVGDAZBTIVRTGO-UONOGXRCSA-N 3-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-methoxy-6-[(2s)-2-methylpiperazin-1-yl]pyridin-3-yl]pyridin-2-amine Chemical compound C1([C@@H](C)OC=2C(N)=NC=C(C=2)C2=CN=C(C=C2OC)N2[C@H](CNCC2)C)=C(Cl)C=CC(F)=C1Cl BVGDAZBTIVRTGO-UONOGXRCSA-N 0.000 description 1
- WWNMSIWLLBJLQW-UHFFFAOYSA-N 3-[[(2-methylsulfanyl-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]methyl]phenol Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)O)SC WWNMSIWLLBJLQW-UHFFFAOYSA-N 0.000 description 1
- YDDYNUGTRZIDBE-UHFFFAOYSA-N 3-[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]-N-(1-prop-2-enoylpiperidin-4-yl)benzamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NC3=CC=CC(=C3)C(=O)NC3CCN(CC3)C(=O)C=C)N2N=C1 YDDYNUGTRZIDBE-UHFFFAOYSA-N 0.000 description 1
- BHMZMZOMQYFFQL-UHFFFAOYSA-N 3-amino-4-fluorobenzonitrile Chemical compound NC1=CC(C#N)=CC=C1F BHMZMZOMQYFFQL-UHFFFAOYSA-N 0.000 description 1
- GYLKKXHEIIFTJH-UHFFFAOYSA-N 3-cyanobenzoic acid Chemical compound OC(=O)C1=CC=CC(C#N)=C1 GYLKKXHEIIFTJH-UHFFFAOYSA-N 0.000 description 1
- SNMHXSABRFTPOF-UHFFFAOYSA-N 3-nitro-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]benzamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(C1=CC(=CC=C1)[N+](=O)[O-])=O)NC1CCOCC1 SNMHXSABRFTPOF-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YLUGQOCWOPDIMD-UHFFFAOYSA-N 4-(dimethylamino)but-2-enamide Chemical compound CN(C)CC=CC(N)=O YLUGQOCWOPDIMD-UHFFFAOYSA-N 0.000 description 1
- TUQRVKUFLCVKKV-INIZCTEOSA-N 4-N-[(3-aminophenyl)methyl]-2-N-[(3S)-oxan-3-yl]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine Chemical compound CC(C)C1=C2N=C(N[C@H]3CCCOC3)N=C(NCC3=CC(N)=CC=C3)N2N=C1 TUQRVKUFLCVKKV-INIZCTEOSA-N 0.000 description 1
- LKBIYFSEXXWLCX-UHFFFAOYSA-N 4-N-[(5-amino-2-ethylphenyl)methyl]-2-N-(oxan-4-yl)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine Chemical compound NC=1C=CC(=C(CNC2=NC(=NC=3N2N=CC=3C(C)C)NC2CCOCC2)C=1)CC LKBIYFSEXXWLCX-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 1
- PDFYLKPBYWPEDQ-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=C(SC)N=C(Cl)N2N=CC=C21 PDFYLKPBYWPEDQ-UHFFFAOYSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- VAWTVSTXVGCVJW-UHFFFAOYSA-N 5-amino-2-bromobenzonitrile Chemical compound NC1=CC=C(Br)C(C#N)=C1 VAWTVSTXVGCVJW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- JGCHRCABGPCQHO-UHFFFAOYSA-N 8-ethyl-2-methylsulfanyl-N-[(3-nitrophenyl)methyl]pyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound CCC1=C2N=C(SC)N=C(NCC3=CC(=CC=C3)[N+]([O-])=O)N2N=C1 JGCHRCABGPCQHO-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CZVXEAQRYGDPEH-UHFFFAOYSA-N C(C)(C)C=1C=NN2C1N(C(N=C2)S(=O)(=O)C)CC2=CC(=CC=C2)[N+](=O)[O-] Chemical compound C(C)(C)C=1C=NN2C1N(C(N=C2)S(=O)(=O)C)CC2=CC(=CC=C2)[N+](=O)[O-] CZVXEAQRYGDPEH-UHFFFAOYSA-N 0.000 description 1
- IOOYOFXLPVHFKJ-UHFFFAOYSA-N C(C)(C)C=1C=NN2C1N=C(C=C2)NC2CCOCC2 Chemical compound C(C)(C)C=1C=NN2C1N=C(C=C2)NC2CCOCC2 IOOYOFXLPVHFKJ-UHFFFAOYSA-N 0.000 description 1
- AJBCZSGWLVACPU-UHFFFAOYSA-N C(C)(C)C=1C=NN2C1N=C(N=C2)NC2CCOCC2 Chemical compound C(C)(C)C=1C=NN2C1N=C(N=C2)NC2CCOCC2 AJBCZSGWLVACPU-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- 229940126074 CDK kinase inhibitor Drugs 0.000 description 1
- 101150059217 CDK12 gene Proteins 0.000 description 1
- 101150035324 CDK9 gene Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 102000002435 Cyclin T Human genes 0.000 description 1
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 1
- 102100024112 Cyclin-T2 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100023263 Cyclin-dependent kinase 10 Human genes 0.000 description 1
- 102100038113 Cyclin-dependent kinase 14 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
- 102100034741 Cyclin-dependent kinase 20 Human genes 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- 102100034770 Cyclin-dependent kinase inhibitor 3 Human genes 0.000 description 1
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010016935 Follicular thyroid cancer Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000713120 Homo sapiens Cyclin-H Proteins 0.000 description 1
- 101000868333 Homo sapiens Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 101000908138 Homo sapiens Cyclin-dependent kinase 10 Proteins 0.000 description 1
- 101000884374 Homo sapiens Cyclin-dependent kinase 14 Proteins 0.000 description 1
- 101000944357 Homo sapiens Cyclin-dependent kinase 16 Proteins 0.000 description 1
- 101000944345 Homo sapiens Cyclin-dependent kinase 19 Proteins 0.000 description 1
- 101000945708 Homo sapiens Cyclin-dependent kinase 20 Proteins 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 101000945639 Homo sapiens Cyclin-dependent kinase inhibitor 3 Proteins 0.000 description 1
- 101000909198 Homo sapiens DNA polymerase delta catalytic subunit Proteins 0.000 description 1
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 1
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010023347 Keratoacanthoma Diseases 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 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
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- DNSNIVPZDDXYEL-UHFFFAOYSA-N N-[(3-aminophenyl)methyl]-2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC(N)=CC=C3)N2N=C1 DNSNIVPZDDXYEL-UHFFFAOYSA-N 0.000 description 1
- PTQQIMLEOKZRMG-UHFFFAOYSA-N N-[(3-aminophenyl)methyl]-2-methoxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound NC=1C=C(CNC2=NC(=NC=3N2N=CC=3C(C)C)OC)C=CC=1 PTQQIMLEOKZRMG-UHFFFAOYSA-N 0.000 description 1
- DCUXBIVXPGSTSD-UHFFFAOYSA-N N-[(3-aminophenyl)methyl]-8-ethyl-2-(1-methylpiperidin-4-yl)oxypyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound CCC1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC(N)=CC=C3)N2N=C1 DCUXBIVXPGSTSD-UHFFFAOYSA-N 0.000 description 1
- GXNTVXCERGZZAV-UHFFFAOYSA-N N-[3-[(2-methylsulfanyl-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]phenyl]-4-nitrobenzamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NC=1C=C(C=CC=1)NC(C1=CC=C(C=C1)[N+](=O)[O-])=O)SC GXNTVXCERGZZAV-UHFFFAOYSA-N 0.000 description 1
- INIDDXNITHWSCB-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]piperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCCCN4)=C3)N2N=C1 INIDDXNITHWSCB-UHFFFAOYSA-N 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- FNEMCDROMYCDBF-UHFFFAOYSA-N N=C=S.CCOC(O)=O Chemical compound N=C=S.CCOC(O)=O FNEMCDROMYCDBF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- UQONAEXHTGDOIH-AWEZNQCLSA-N O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 Chemical compound O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 UQONAEXHTGDOIH-AWEZNQCLSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000002508 Peptide Elongation Factors Human genes 0.000 description 1
- 108010068204 Peptide Elongation Factors Proteins 0.000 description 1
- 241001503951 Phoma Species 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010012271 Positive Transcriptional Elongation Factor B Proteins 0.000 description 1
- 102000019014 Positive Transcriptional Elongation Factor B Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 101100273253 Rhizopus niveus RNAP gene Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 206010043276 Teratoma Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000005122 aminoalkylamino group Chemical group 0.000 description 1
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000005735 apoptotic response Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005128 aryl amino alkyl group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast 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
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 125000001108 carbamothioyl group Chemical group C(N)(=S)* 0.000 description 1
- 150000001717 carbocyclic compounds Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011361 granulated particle Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000003121 in-cell western assay Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 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
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 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
- 210000005036 nerve Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 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
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 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
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- RIXVESSVKLKKFV-UHFFFAOYSA-N piperazine-1,4-dicarboxylic acid Chemical compound OC(=O)N1CCN(C(O)=O)CC1 RIXVESSVKLKKFV-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- IIKFXOLJMNWWCH-UHFFFAOYSA-N piperidine-1,4-dicarboxylic acid Chemical compound OC(=O)C1CCN(C(O)=O)CC1 IIKFXOLJMNWWCH-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000001513 prostate squamous cell carcinoma Diseases 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- AKQXKEBCONUWCL-QMMMGPOBSA-N tert-butyl (3s)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)C1 AKQXKEBCONUWCL-QMMMGPOBSA-N 0.000 description 1
- JZNWQLLPLOQGOI-UHFFFAOYSA-N tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C(F)C1 JZNWQLLPLOQGOI-UHFFFAOYSA-N 0.000 description 1
- NCIQNWYJLAAFAH-UHFFFAOYSA-N tert-butyl 4-carbonochloridoylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(Cl)=O)CC1 NCIQNWYJLAAFAH-UHFFFAOYSA-N 0.000 description 1
- LUKQTNVNMALRMG-UHFFFAOYSA-N tert-butyl 4-carbonochloridoylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(Cl)=O)CC1 LUKQTNVNMALRMG-UHFFFAOYSA-N 0.000 description 1
- LIYMTLVBAVHPBU-UHFFFAOYSA-N tert-butyl n-(4-hydroxybutyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCO LIYMTLVBAVHPBU-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005029 transcription elongation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Description
本発明は、CDK7、CDK9、CDK12、CDK13およびCDK18を含む、選択的転写サイクリン依存性キナーゼ(CDK)、より具体的には転写サイクリン依存性キナーゼ−7(CDK7)の活動を抑制する化合物に関係する。本発明は、また、本発明の化合物を含む許容医薬組成物、及び選択的転写CDKに関連する疾患や障害の処置における前記組成物の使用方法を提供する。
式中、
XはCHまたはNであり;
環Aは、単環式か二環式アリール、ヘテロアリールまたはヘテロシクロアルキルであり;
環Bはシクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、または不在であり;
R1は水素、アルキルまたはシクロアルキルであり;
R2は、随意置換されたアルキル、シクロアルキルまたはヘテロシクロアルキルであり;ここで、随意置換基はアミノ、ハロ、ヒドロキシ、アルキル、アルコキシル、アルコキシアルコキシル、アルキルアミノ、シアノ、ニトロ、またはハロアルキルであり;
それぞれ独立状態のR3は、ハロ、アルキル、ヒドロキシ、アルコキシ、アミノ、アルキルアミノ、シアノ、ニトロ、ハロアルキルであり;
それぞれ独立状態のR4は、ハロ、アルキル、ヒドロキシ、アルコキシ、−(NH)q−S(O)2−CH=CH2、(NH)q−CH2−CH=CH−C(O)−NRaRb、
ここで、それぞれ独立状態のR5とR5”は水素またはアルキルであり;R5’は水素、ハロ、アルキル、アルコキシアルキルまたは−CH2−NRaRbであり;
R6は水素またはアルキルであり;
RaとRbは各自に水素またはアルキルであり;またはRaおよびRbは、それらと結合している窒素原子と一緒になって、O、SおよびNから選択される0〜2個の付加的なヘテロ原子を有する随意置換された複素環を形成し;その随意置換基は、1つ以上のアルキルまたはハロであり;
L1は−O−、−S−、−NH−または不在であり;
L2は不在または随意置換されたC1−C6アルキレンであり、そのアルキレンの1つ以上のメチレン単位は、−C(O)−、−O−、−N(R7)−またはシクロアルキレンで随意かつ各自に置換されている;R7は水素またはアルキルであり;
mは0〜1であり;
nは0、1または2であり;
pは1、2または3であり;そして
qは0〜1である。
他に定義されていない限り、本明細書に使用されている全ての技術的および科学的用語は、本発明の主目的分野の熟練者が一般的に理解されるのと同じ意味である。仕様と添付の請求項にて用いられているように、逆に指定しない限り、以下の用語は、本発明の理解を容易にするための意味を示している。
式中、
XはCHまたはNであり;
環Aは、単環式か二環式アリール、ヘテロアリールまたはヘテロシクロアルキルであり;
環Bはシクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、または不在であり;
R1は水素、アルキルまたはシクロアルキルであり;
R2は、随意置換されたアルキル、シクロアルキルまたはヘテロシクロアルキルであり;ここで、随意置換基はアミノ、ハロ、ヒドロキシ、アルキル、アルコキシル、アルコキシアルコキシル、アルキルアミノ、シアノ、ニトロ、またはハロアルキルであり;
それぞれ独立状態のR3は、ハロ、アルキル、ヒドロキシ、アルコキシ、アミノ、アルキルアミノ、シアノ、ニトロ、ハロアルキルであり;
それぞれ独立状態のR4は、ハロ、アルキル、ヒドロキシ、アルコキシ、−(NH)q−S(O)2−CH=CH2、(NH)q−CH2−CH=CH−C(O)−NRaRb、
ここで、それぞれ独立状態のR5とR5”は水素またはアルキルであり;R5’は水素、ハロ、アルキル、アルコキシアルキルまたは−CH2−NRaRbであり;
R6は水素またはアルキルであり;
RaとRbは各自に水素またはアルキルであり;またはRaおよびRbは、それらと結合している窒素原子と一緒になって、O、SおよびNから選択される0〜2個の付加的なヘテロ原子を有する随意置換された複素環を形成し;その随意置換基は、1つ以上のアルキルまたはハロであり;
L1は−O−、−S−、−NH−または不在であり;
L2は不在または随意置換されたC1−C6アルキレンであり、そのアルキレンの1つ以上のメチレン単位は、−C(O)−、−O−、−N(R7)−またはシクロアルキレンで随意かつ各自に置換されており;そこでR7は水素またはアルキルであり;
mは0〜1であり;
nは0、1または2であり;
pは1、2または3であり;そして
qは0〜1である。
式中、
環A、環B、L1、L2、R1、R2、R3、R4、R6、m、n、及びpは、化学式(I)に定義されているものと同じである。
式中、
X、環B、L1、L2、R1、R2、R3、R4、R6、m、n、及びpは、化学式(I)に定義されているものと同じである。
式中、
R2は、随意シクロアルキルに置換、または随意ヘテロシクロアルキルに置換され;
X、環A、環B、L2、R1、R3、R4、R6、m、n、及びpは、化学式(I)に定義されているものと同じである。
式中、
R2は、随意シクロアルキルに置換、または随意ヘテロシクロアルキルに置換され;
X、環B、L2、R1、R3、R4、R6、m、n、及びpは、化学式(I)に定義されているものと同じである。
式中、
X、環B、L2、R1、R3、R4、R6、m、n、及びpは、化学式(I)に定義されているものと同じである。
式中、
X、L1、R1、R2、R3、R4、R6、m、n、及びpは、化学式(I)に定義されているものと同じである。
本発明の化合物は、合成化学物質手順で調製される。例示については本明細書に記載する。過程における段階順序には幅があること、試薬、溶媒と反応条件については具体的に記載されているものに置換される可能性があること、不安定な部分については必要に応じて保護・脱保護される可能性があることが、理解されるものとする。
化学式−1.0の化合物は、DIPEA、TEAなどの適当な塩基存在下で、またACN、1,4−ジオキサン、DMSO、DCEなどの適当な極性溶媒の存在下で化学式−1.1によりおおよそ20℃から35℃の温度下で2時間から24時間にわたり扱うことができ、化学式−1.2の化合物を実現する。化学式−1.2の化合物は、さらにDCM、CHCl3、DCEなどの適当な溶媒の存在下でmCPBAによりおおよそ0℃から35℃の温度下で2時間から24時間にわたり取り扱うことができ、化学式−1.3の化合物を実現する。溶剤(NMPのような溶剤)があろうともなかろうとも、化学式1.3の化合物を適当なアミンにより、おおよそ100℃から150℃の温度下で1時間から24時間かけて扱うことで化学式1.4(その中でL1=NH)の化合物を合成することが出来る。また、化学式1.3の化合物をTHF、DMSO、DMF、1,4−ジオキサンまたはジエチルエーテルなどの適切溶媒にありNaH、LiH、KH、K2CO3またはCs2CO3などの適切塩基の存在下で適当なアルコールと、おおよそ−30℃から100℃の温度かで温度下で1時間から24時間かけて扱うことで化学式1.4(その中でL1=O)の化合物が合成することが出来る。化学式−1.4の化合物は、THF:MeOH:水、THF:EtOH:水、メタノール:水、エタノール:水、メタノールまたはエタノールなどの適切な溶媒配合比率を用いて、おおよそ20℃から120℃の温度下で約1時間から24時間かけて亜鉛末/NH4ClまたはFe/NH4ClまたはZn/aq.NH4Clのような適当な試薬の存在下でニトロ基の還元を経て、化学式1.5の化合物を実現する。
化学式1.5の化合物は、化学式−1.0の化合物を使用し化学式2.1の化合物と反応させることで準備され、ルート−Aに示しているように化学式の化合物1.4の準備に似た手順を使用することで化学式2.4の化合物の形成まで進めることが出来る。結果として得られた化学式2.4の化合物はさらに、おおよそ20℃から35℃の温度下で約2時間から24時間かけてDCM、クロロホルム、THFまたは1,4−ジオキサンなどのような適当な溶媒の存在下でTFAなどの適当な試薬の存在下でBOC(ブチルオキシカルボニル)の脱保護を経て、化学式−1.5の化合物を実現する。
スキーム−Iとスキーム−IIのルート−A・ルート−Bに示す手順に従い、化学式−1.5の化合物を開始剤として使用し、一般的な化学式(I)に沿う化合物を調製することが出来る。
化学式(I)の化合物は、DMF、THF、DMSO、DCMなどの適当な溶媒において、DIPEAまたはTEAのような適当な塩基の存在下で、HATU、EDC.HCl−HOBtなどの適当な試薬の存在下にある適切な酸を用いて、おおよそ20℃から35℃の温度下で約1時間から24時間かけて化学式−1.5の化合物を処理することで、合成することが出来る。
化学式3.4の化合物は、スキーム−Iルート−Aに示す手順に従い調製された。結果として得られた化学式−3.4の化合物は、おおよそ20℃から35℃の温度下で約2時間から24時間かけてDCM、クロロホルム、THFまたは1,4−ジオキサンなどの適当な溶媒の存在下で、TFAなどの適当な試薬の存在下にあるBOCの脱保護を経て、化学式−3.5の化合物を実現する。DCM、クロロホルム、THFまたは1,4−ジオキサンなどの適当な溶媒の存在下で、TEAやDIPEAなどの適当な塩基の存在下にある適切な酸塩化物を用いて、おおよそ20℃〜35℃の温度下で2時間から24時間かけて化学式−3.5の化合物を処理し、化学式−Iの化合物を実現することができる。
以下の略語はそれぞれ本明細書における定義を指す。LDA(リチウムジイソプロピルアミド)、K2CO3(炭酸カリウム)、PdCl2(dppf)2−DCM(1,1’−Bis(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)、ジクロロメタン複合体)、DHP(3,4−ジヒドロ−2H−ピラン)、PTSA(p−トルエンスルホン酸)、EDCI(1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド、Dikis(Bis(トリフェニルホスフィン)パラジウム(II)二塩化物)、NH3溶液(アンモニア水)、Prep Column(分取カラム)、Prep TLC(分取用薄層クロマトグラフィー)、rt(保持時間)、RT(室温)、DMF(ジメチルホルムアミド)、h(時間)、LC−MS(液体クロマトグラフィー質量分光法)、NaOH(水酸化ナトリウム)、Na2SO4(硫酸ナトリウム)、ACN/CH3CN(アセトニトリル)、HCl(塩化水素)、THF(テトラヒドロフラン)、DCM(ジクロロメタン)、TFA(トリフルオロ酢酸)、TLC(薄層クロマトグラフィー)、DIPEA(ジイソプロピルエチルアミン)、DMSO−d6(ジメチル スルホキシド−d)、HATU(1−[Bis(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−oxid−ヘキサフルオロホスフェート)、Boc2O(ジターシャルブチルジカルボナート)、HPLC(高圧液体クロマトグラフィー)、NaHCO3(炭酸水素ナトリウム)、NaH(水素化ナトリウム)、SEM塩化化合物(2−(トリメチルシリル)エトキシ 塩化メチル)、Cs2CO3(炭酸セシウム)、BINAP(2,2’−Bis(ジフェニルホスフィノ)−1,1’−ビナフチル)、Pd2(dba)3(Tris(ジベンジリデンアセトン)ジパラジウム(0))、TEA(トリエチルアミン)、TPP(トリフェニルホスフィン)、DIAD(ジイソプロピル・アゾジカルボン酸塩)、LiBH4(水素化ホウ素リチウム)、TMSCl(クロロトリメチルシラン)。
本発明が特定の前例により例示されたが、それに制限された解釈ではなく、先に開示されるように本発明には一般的な領域が含まれている。その精神や範囲を逸脱しない範囲で、様々な修正とその展開を行う。
質量スペクトル:LC/MS Agilent社 6120 四重極子 LC/MS
1H−NMR:Varian社 400 MHz
化学式(I)の化合物向け手順は以下に段階的に詳しく記載されており、本発明に準じた化合物製造手順に関する多様な中間体の一般的合成が含まれる。
化合物のCDK7キナーゼ活性を抑制する能力を、アメリカのInvitrogenから得た5nMのCDK7 / CycH / MNAT1を用いるTR−FRETアッセイで試験した。試験化合物をキナーゼと共に室温で60分間プレインキュベートした。 インキュベーション後、基質混合物[100nM超軽量MBP(Perkin Elmer、アメリカ)および1mM ATP(Sigma)]を添加した。キナーゼ反応の60分後に40mM EDTAを添加することにより、上記の反応を停止した。1nM Eu標識ホスホ−MBP抗体[Perkin Elmer、アメリカ]を添加し、よく混合し、615nmおよび665nmでの蛍光放射[340nmで励起]を測定した。アッセイの最終DMSO濃度は1%だった。IC50を算出するために、試験化合物の10mM DMSOストック溶液の1/3段階希釈によって適切な濃度を作成した。すべての蛍光測定はVictor 3マルチラベルカウンター[Perkin Elmer、アメリカ]で行った。GRaphPad PrismソフトウェアV5を使用して、シグモイド用量反応曲線フィッティングに線量応答データをフィッティングすることにより、IC50を算出した。CDK7を不可逆的に抑制する化合物を確認するために、3つの時点(20,60および180分)で化合物を酵素でプレインキュベートし、上記のアッセイを行うことによって、時間依存的な抑制の研究を行った。
マウスに移植されたMV4−11異種移植片腫瘍の生長を抑制するCDK7阻害剤の効果を評価した。簡単に言うと、MV4−11細胞を、10%FBS(Invitrogen)および1%ペニシリンストレプトマイシン(Invitorgen)を補充したイスコフ改変ダルベッコ培地(Sigma Aldrich)で生長させた。腫瘍を作るために、15X106 MV4−11細胞を、オスの胸腺欠損ヌードマウス(Envigo)の右脇腹の後ろに200μlの1:1 HBSS(Sigma:H4641)およびECMゲル(Corning)を皮下注射した。腫瘍体積を週3回測定し、体重を毎日モニターした。腫瘍体積を推定するために、異種移植片腫瘍の長さ(D)と幅(d)を、カリパスを用いて手動で測定し、腫瘍体積=(D×d2)/2の式を用いて計算した。平均腫瘍体積が約250mm3に達した時点で処置を開始した。動物を腫瘍体積に基づいてランダム化し、各々7匹の2つのグループに分けた。有効性を評定するために、化合物−115を1日1回(q24h/ qd スケジュール)腹腔内に投与した。処置期間は14日間であり、処置期間中に観察された腫瘍体積の変化に基づいて総体的な有効性を評定した。処置群と対照群を比較するために、ダネットの多重比較検定と一元配置分散分析を用いて腫瘍体積を分析した。結果をグラフ(図−1)に示す。
選択された化合物を添加する前に、25000個の細胞(MDA−MB−231/NCI−H358)を96ウェルの黒クリアボトムプレートに播種し、一晩インキュベートした。選択された化合物の3倍希釈液をDMSOで10μMから希釈し、細胞に添加し、37℃、5%CO2のインキュベーターで4時間インキュベートした。細胞を100μlのリン酸緩衝化生理食塩水(sigma#P3813)で1回洗浄し、100μl/ウェルの4%パラホルムアルデヒドで室温、暗所で60分間固定した。細胞を100μlの洗浄バッファー(Wash Buffer)(0.1%トリトン X−100を含むPBS)で3回洗浄し、その後ブロッキングバッファー(Blocking Buffer)(PBSTに5%BSA)中に室温で2時間ブロックした。細胞を、ブロッキングバッファー(Blocking Buffer)中のPhospho RNA Pol II(S5)(Millipore#04−1572、Abcam#5131)またはPhospho RNA Pol II(Ser−2)、抗体(Bethyl labs#A300−654−A)により4℃で一晩染色した。インキュベーション後の細胞をDelifia洗浄バッファー(Wash Buffer)(Perkin Elmer#4010−0010)で洗浄した。細胞をアッセイバッファー(Assay buffer)(Perkin Elmer#1244−111)中でLANCE二次抗体(LANCE(登録商標) Eu−W1024 perkin elmer # AD−0076 for phospho Ser−5 CTD RNA pol−II and Delfia Eu−N1 anti Rabbit IgG Perkin elmer # AD0106 for phospho Ser−2 CTD RNA pol−II)で2時間処置し、インキュベーション後に細胞をDelfia洗浄バッファー(Wash Buffer)で3回洗浄し、増強溶液(Enhancement solution)(Perkin Elmer#1244−105)を添加し、20分間インキュベートした。ユーロピウムの測定値をVictor−3器具から読み取った。Hoechst dye(0.5μg/ ml)を用いて細胞を標準化した。
Claims (32)
- 化学式(I)の化合物:
式中、
XはCHまたはNであり;
環Aは、単環式か二環式アリール、ヘテロアリールまたはヘテロシクロアルキルであり;
環Bはシクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、または不在であり;
R1は水素、アルキルまたはシクロアルキルであり;
R2は、随意置換されたアルキル、シクロアルキルまたはヘテロシクロアルキルであり;ここで、随意置換基はアミノ、ハロ、ヒドロキシ、アルキル、アルコキシル、アルコキシアルコキシル、アルキルアミノ、シアノ、ニトロ、またはハロアルキルであり;
それぞれ独立状態のR3は、ハロ、アルキル、ヒドロキシ、アルコキシ、アミノ、アルキルアミノ、シアノ、ニトロ、ハロアルキルであり;
それぞれ独立状態のR4は、ハロ、アルキル、ヒドロキシ、アルコキシ、−(NH)q−S(O)2−CH=CH2、(NH)q−CH2−CH=CH−C(O)−NRaRb、
式中、それぞれ独立状態のR5とR5”は水素またはアルキルであり;R5’は水素、ハロ、アルキル、アルコキシアルキルまたは−CH2−NRaRbであり;
R6は水素またはアルキルであり;
RaとRbは独立して水素またはアルキルであり;またはRaおよびRbは、それらと結合している窒素原子と一緒になって、O、SおよびNから選択される0〜2個の付加的なヘテロ原子を有する随意置換された複素環を形成し;その随意置換基は、1つ以上のアルキルまたはハロであり;
L1は−O−、−S−、−NH−または不在であり;
L2は不在または随意置換されたC1−C6アルキレンであり、そのアルキレンの1つ以上のメチレン単位は、−C(O)−、−O−、−N(R7)−またはシクロアルキレンで随意かつ独立して置換され;R7は水素またはアルキルであり;
mは0〜1であり;
nは0、1または2であり;
pは1、2または3であり;そして
qは0〜1である、化学式(I)の化合物、または、その薬学的に許容可能な塩または立体異性体。 - 前記化学式(I)の化合物が、化学式(IA)の化合物、
式中、環A、環B、L1、L2、R1、R2、R3、R4、R6、m、n、及びpは請求項1に定義されるものと同じであることを特徴とする請求項1の化合物。 - 前記化学式(I)の化合物が、化学式(IB)の化合物、
式中、
X、環B、L1、L2、R1、R2、R3、R4、R6、m、n、及びpは請求項1に定義されるものと同じであることを特徴とする請求項1の化合物。 - 前記化学式(I)の化合物が、化学式(IC)の化合物、
式中、
R2は随意置換されたシクロアルキルまたは随意置換されたヘテロシクロアルキルであり;
X、環A、環B、L2、R1、R3、R4、R6、m、n、及びpは請求項1に定義されるものと同じであることを特徴とする請求項1の化合物。 - 前記化学式(I)の化合物が、化学式(ID)の化合物、
式中、
R2は随意置換されたシクロアルキルまたは随意置換されたヘテロシクロアルキルであり;
X、環B、L2、R1、R3、R4、R6、m、n、及びpは請求項1に定義されるものと同じであることを特徴とする請求項1の化合物。 - 前記化学式(I)の化合物が、化学式(IE)の化合物、
式中、
X、環B、L2、R1、R3、R4、R6、m、n、及びpは請求項1に定義されるものと同じであることを特徴とする請求項1の化合物。 - 前記化学式(I)の化合物が、化学式(IF)の化合物、
式中、
X、L1、R1、R2、R3、R4、R6、m、n、及びpは請求項1に定義されるものと同じであることを特徴とする請求項1の化合物。 - 前記環Aがフェニル、ピリジルまたはピペリジニルである請求項1,2又は4のいずれか一つに記載の化合物。
- 前記環Bがシクロアルキル、アリール、ヘテロシクロアルキルまたはヘテロアリールである請求項1−6のいずれか一つに記載の化合物。
- 前記L1がNHまたはOである請求項1−3又は7のいずれか一つに記載の化合物。
- 前記R2が随意置換されたシクロアルキルまたは随意置換されたヘテロシクロアルキルである請求項1−5又は7のいずれか一つに記載の化合物。
- 前記シクロアルキルが好ましくはシクロヘキシルであり、前記ヘテロシクロアルキルが好ましくはN−メチル−4−ピペリジニルもしくはテトラヒドロ−4−ピラニルである請求項11に記載の化合物。
- 前記R1が水素またはアルキルであり; そのアルキルが好ましくはイソプロピルである請求項1−7のいずれか一つに記載の化合物。
- R4が
- R5’が好ましくは−CH2−NRaRbであり、RaおよびRbは独立して水素またはアルキルである請求項14に記載の化合物。
- 前記RaおよびRbが、それらと結合している窒素原子と一緒になって、O、SおよびNから選択される0〜2個の付加的なヘテロ原子を有する随意置換された複素環を形成する請求項15に記載の化合物。
- 以下の化合物、またはその薬学的に許容可能な塩または立体異性体から構成されるグループから選択された化合物。
- 以下の化合物、またはその薬学的に許容可能な塩または立体異性体から構成されるグループから選択された化合物。
- 請求項1〜18のいずれか一つに記載の化合物またはその薬学的に許容可能な塩または立体異性体と、少なくとも一つの薬学的に許容可能な担体または賦形剤とを含む医薬組成物。
- 薬剤として使用するための、請求項1〜18のいずれか一つに記載の化合物またはその薬学的に許容可能な塩もしくは立体異性体。
- 癌を処置するための医薬の製造における、請求項1〜18のいずれか一つに記載の化合物の使用。
- 選択的転写CDKの異常活性に関連する疾病や症状に罹患している被験体を処置するのに使用する請求項19〜21のいずれか一つに記載の医薬組成物または薬物。
- 選択的転写CDK7の異常活性に関連する疾病や症状に罹患している被験体を処置するための請求項22に記載の医薬組成物または薬物。
- 請求項1〜18のいずれか一つに記載の化合物の治療有効量を投与する工程を含む、被験体の選択的転写CDK媒介性の障害や疾患や疾病を処置する方法。
- 請求項1〜18のいずれか一つに記載の化合物を投与する工程を含む、被験体の選択的転写CDKを抑制する方法。
- 被験体がヒトを含む哺乳動物である請求項24又は25に記載の方法。
- 選択的転写CDK媒介性の障害や疾患や疾病が、癌、炎症性疾患、自己炎症性疾患または感染性疾患からなるグループから選択されている請求項24又は25に記載の方法。
- 癌が、乳癌、肝臓癌、肺癌、結腸癌、腎臓癌、膀胱癌、小細胞肺癌、非小細胞性肺癌、頭頸部癌、甲状腺癌、食道癌、胃癌、膵臓癌、卵巣癌、胆嚢癌、子宮頸部癌、前立腺癌、皮膚癌、および扁平上皮癌を含む癌腫;白血病、急性リンパ性白血病、急性リンパ芽球性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、B細胞リンパ腫、T細胞リンパ腫、毛状細胞リンパ腫、骨髄腫、マントル細胞リンパ腫およびバーキットリンパ腫を含むリンパ系の造血器腫瘍;急性および慢性の骨髄性白血病、骨髄異形成症候群および急性前骨髄球性白血病を含む骨髄系の造血腫瘍;線維肉腫および横紋筋肉腫を含む、間葉原発性の腫瘍;アストロチーマ、神経芽腫、神経膠腫および神経鞘腫を含む中枢および末梢神経系の腫瘍;精上皮腫、メラノーマ、骨肉腫、奇形癌腫、角膜腫瘍腫、異種異型腫、甲状腺濾胞がんおよびカポジ肉腫を含む他の腫瘍からなるグループから選択されている請求項27に記載の方法。
- 抗増殖剤、抗癌剤、免疫抑制剤および鎮痛剤から独立して選択された1つまたは複数の付加的な化学療法剤を必要のある被験体に投与する工程を更に含む、請求項24〜28のいずれか一つに記載の方法。
- 選択的転写CDKがCDK7、CDK9、CDK12、CDK13またはCDK18である請求項24〜27のいずれか一つに記載の方法。
- 薬剤として使用する請求項1〜18のいずれか一つに記載の化合物。
- 癌処置に使用する請求項1〜18のいずれか一つに記載の化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1128/CHE/2015 | 2015-03-09 | ||
IN1128CH2015 | 2015-03-09 | ||
PCT/IB2016/051302 WO2016142855A2 (en) | 2015-03-09 | 2016-03-08 | Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives as cdk inhibitors |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018507877A true JP2018507877A (ja) | 2018-03-22 |
JP2018507877A5 JP2018507877A5 (ja) | 2020-04-30 |
JP6789962B2 JP6789962B2 (ja) | 2020-11-25 |
Family
ID=56879301
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017546949A Active JP6789962B2 (ja) | 2015-03-09 | 2016-03-08 | CDK阻害剤としてのピラゾロ[1,5−a][1,3,5]トリアジンとピラゾロ[1,5−a]ピリミジン誘導体 |
Country Status (7)
Country | Link |
---|---|
US (2) | US11186576B2 (ja) |
EP (1) | EP3268000B1 (ja) |
JP (1) | JP6789962B2 (ja) |
CN (1) | CN107530329B (ja) |
CA (1) | CA2978170C (ja) |
ES (1) | ES2899196T3 (ja) |
WO (1) | WO2016142855A2 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018515434A (ja) * | 2015-03-27 | 2018-06-14 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | サイクリン依存性キナーゼの阻害剤 |
JP2021521129A (ja) * | 2018-04-11 | 2021-08-26 | キュリエント カンパニー, リミテッド | 薬学的に活性なピラゾロ−トリアジン誘導体および/またはピラゾロ−ピリミジン誘導体 |
US11826365B2 (en) | 2009-12-29 | 2023-11-28 | Dana-Farber Cancer Institute, Inc. | Type II raf kinase inhibitors |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2822935B1 (en) | 2011-11-17 | 2019-05-15 | Dana-Farber Cancer Institute, Inc. | Inhibitors of c-jun-n-terminal kinase (jnk) |
EP3057956B1 (en) | 2013-10-18 | 2021-05-05 | Dana-Farber Cancer Institute, Inc. | Polycyclic inhibitors of cyclin-dependent kinase 7 (cdk7) |
EP3129371B1 (en) * | 2014-04-05 | 2020-07-29 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
WO2016105528A2 (en) | 2014-12-23 | 2016-06-30 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
EP3268000B1 (en) * | 2015-03-09 | 2021-08-04 | Aurigene Discovery Technologies Limited | Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives as cdk inhibitors |
EP4019515A1 (en) | 2015-09-09 | 2022-06-29 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinases |
JP7216705B2 (ja) | 2017-07-28 | 2023-02-02 | ニンバス ラクシュミ, インコーポレイテッド | Tyk2阻害剤およびその使用方法 |
TWI703149B (zh) * | 2017-11-16 | 2020-09-01 | 美商美國禮來大藥廠 | 用於抑制cdk7之化合物 |
CA3095568A1 (en) * | 2018-03-29 | 2019-10-03 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US11945822B2 (en) | 2018-04-11 | 2024-04-02 | Qurient Co., Ltd. | Pyrazolo-triazine and/or pyrazolo-pxrimidine derivatives as selective inhibitor of cyclin dependent kinase |
EA039950B1 (ru) * | 2018-07-20 | 2022-03-31 | Эли Лилли Энд Компани | Соединения, пригодные для ингибирования cdk7 |
CN110835345A (zh) * | 2018-08-17 | 2020-02-25 | 中国科学院上海药物研究所 | 一类细胞周期依赖性激酶的降解剂、其制备方法、药物组合物及其用途 |
JP7385658B2 (ja) | 2018-10-30 | 2023-11-22 | クロノス バイオ インコーポレイテッド | Cdk9活性を調節するための化合物、組成物、および方法 |
US20220144841A1 (en) * | 2019-03-13 | 2022-05-12 | The Translational Genomics Research Institute | Trisubstituted pyrazolo [1,5-a] pyrimidine compounds as cdk7 inhibitors |
CN112125908B (zh) * | 2019-06-25 | 2023-11-03 | 隆泰申医药科技(南京)有限公司 | Cdk激酶抑制剂、其制备方法、药物组合物和应用 |
TW202146416A (zh) * | 2019-12-11 | 2021-12-16 | 德商拜耳廠股份有限公司 | 吡唑并三𠯤 |
KR20220137002A (ko) * | 2019-12-20 | 2022-10-11 | 에보포인트 바이오사이언시스 컴퍼니 리미티드 | 헤테로고리 화합물 및 그의 약제학적 조성물, 제조 방법, 중간체 및 용도 |
CN110950871B (zh) * | 2019-12-25 | 2022-05-17 | 陕西师范大学 | 2-取代-4-芳氨基吡唑并三嗪衍生物及制备抗肿瘤药物的应用 |
CN111393447B (zh) * | 2020-05-14 | 2021-01-15 | 苏州信诺维医药科技有限公司 | 一种嘧啶并吡唑类化合物、其制备方法及应用 |
TWI783480B (zh) * | 2020-05-27 | 2022-11-11 | 美商美國禮來大藥廠 | 用於抑制cdk7之化合物 |
CN114133394B (zh) * | 2020-08-12 | 2023-12-08 | 赛诺哈勃药业(成都)有限公司 | 一种选择性针对细胞周期依赖性激酶12活性的化合物、制备方法及医药用途 |
WO2022033552A1 (zh) * | 2020-08-12 | 2022-02-17 | 隆泰申医药科技(南京) 有限公司 | Cdk激酶抑制剂、其制备方法、药物组合物和应用 |
WO2022214701A1 (en) * | 2021-04-09 | 2022-10-13 | Universität Basel | Triazine derivative as covalent inhibitors of pi3k |
CN115340524A (zh) * | 2021-05-14 | 2022-11-15 | 重庆博腾制药科技股份有限公司 | 一种(s)-去甲烟碱甲基化制备(s)-尼古丁的方法 |
WO2022266418A1 (en) * | 2021-06-17 | 2022-12-22 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Triazine inhibitors of cyclin-dependent kinases |
CN113801119B (zh) * | 2021-08-30 | 2022-09-30 | 新乡医学院 | 一种吡唑并[1,3,5]三嗪类化合物的合成方法 |
CN114181217B (zh) * | 2022-01-10 | 2022-12-27 | 陕西师范大学 | 吡唑并[1,5-a][1,3,5]三嗪衍生物及其盐和在制备抗癌药物中的应用 |
WO2023227125A1 (zh) * | 2022-05-26 | 2023-11-30 | 杭州德睿智药科技有限公司 | 作为CDKs抑制剂的新型并杂环类新化合物及其应用 |
WO2024066984A1 (zh) * | 2022-09-30 | 2024-04-04 | 楚浦创制(武汉)医药科技有限公司 | 三并环类衍生物、药物组合物以及应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010529140A (ja) * | 2007-06-05 | 2010-08-26 | エモリー・ユニバーシテイ | サイクリン依存性キナーゼの選択的阻害剤 |
JP2012520288A (ja) * | 2009-03-11 | 2012-09-06 | セントレ・ナショナル・デ・ラ・レシェルシェ・サイエンティフィーク | ピラゾロ[1,5−a]−1,3,5−トリアジン誘導体、その調製、及びその治療的使用方法 |
EP2634190A1 (en) * | 2012-03-01 | 2013-09-04 | Lead Discovery Center GmbH | Pyrazolo-triazine derivatives as selective cyclin-dependent kinase inhinitors |
WO2014063068A1 (en) * | 2012-10-18 | 2014-04-24 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
WO2014149164A1 (en) * | 2013-03-15 | 2014-09-25 | Celgene Avilomics Research, Inc. | Mk2 inhibitors and uses thereof |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6194410B1 (en) * | 1998-03-11 | 2001-02-27 | Hoffman-La Roche Inc. | Pyrazolopyrimidine and pyrazolines and process for preparation thereof |
YU9602A (sh) | 1999-08-12 | 2004-11-25 | Pharmacia Italia S.P.A. | Derivati 3(5)-amino-pirazola, postupak za njihovu izradu i njihova upotreba kao antitumornih agenasa |
WO2005026129A1 (en) | 2003-09-15 | 2005-03-24 | Gpc Biotech Ag | Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases |
JP2008526723A (ja) | 2004-12-30 | 2008-07-24 | アステックス、セラピューティックス、リミテッド | Cdk、gsk及びオーロラキナーゼの活性を調節するピラゾール誘導体 |
US8110573B2 (en) | 2004-12-30 | 2012-02-07 | Astex Therapeutics Limited | Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases |
US20070078136A1 (en) | 2005-09-22 | 2007-04-05 | Bristol-Myers Squibb Company | Fused heterocyclic compounds useful as kinase modulators |
US7517882B2 (en) * | 2006-09-18 | 2009-04-14 | Polaris Group | Protein kinase inhibitors |
AU2009266806A1 (en) | 2008-07-03 | 2010-01-07 | Exelixis Inc. | CDK modulators |
WO2012045195A1 (en) | 2010-10-09 | 2012-04-12 | Abbott Laboratories | Pyrrolopyrimidines as fak and alk inhibiters for treatment of cancers and other diseases |
EP2634189A1 (en) | 2012-03-01 | 2013-09-04 | Lead Discovery Center GmbH | Pyrazolo-triazine derivatives as selective cyclin-dependent kinase inhibitors |
EP3129371B1 (en) | 2014-04-05 | 2020-07-29 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
EP3268000B1 (en) * | 2015-03-09 | 2021-08-04 | Aurigene Discovery Technologies Limited | Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives as cdk inhibitors |
US10550121B2 (en) | 2015-03-27 | 2020-02-04 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinases |
CN108024970B (zh) * | 2015-06-04 | 2021-10-01 | 奥瑞基尼探索技术有限公司 | 用作cdk抑制剂的经过取代的杂环衍生物 |
-
2016
- 2016-03-08 EP EP16761176.3A patent/EP3268000B1/en active Active
- 2016-03-08 US US15/557,028 patent/US11186576B2/en active Active
- 2016-03-08 WO PCT/IB2016/051302 patent/WO2016142855A2/en active Application Filing
- 2016-03-08 ES ES16761176T patent/ES2899196T3/es active Active
- 2016-03-08 CN CN201680014422.1A patent/CN107530329B/zh active Active
- 2016-03-08 CA CA2978170A patent/CA2978170C/en active Active
- 2016-03-08 JP JP2017546949A patent/JP6789962B2/ja active Active
-
2021
- 2021-10-01 US US17/492,282 patent/US20220281871A1/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010529140A (ja) * | 2007-06-05 | 2010-08-26 | エモリー・ユニバーシテイ | サイクリン依存性キナーゼの選択的阻害剤 |
JP2012520288A (ja) * | 2009-03-11 | 2012-09-06 | セントレ・ナショナル・デ・ラ・レシェルシェ・サイエンティフィーク | ピラゾロ[1,5−a]−1,3,5−トリアジン誘導体、その調製、及びその治療的使用方法 |
EP2634190A1 (en) * | 2012-03-01 | 2013-09-04 | Lead Discovery Center GmbH | Pyrazolo-triazine derivatives as selective cyclin-dependent kinase inhinitors |
WO2014063068A1 (en) * | 2012-10-18 | 2014-04-24 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
WO2014149164A1 (en) * | 2013-03-15 | 2014-09-25 | Celgene Avilomics Research, Inc. | Mk2 inhibitors and uses thereof |
Non-Patent Citations (1)
Title |
---|
KWIATKOWSKI, NICHOLAS 他: "Targeting transcription regulation in cancer with a covalent CDK7 inhibitor", NATURE (LONDON, UNITED KINGDOM), vol. 511(7511), JPN6019048294, 2014, pages 616 - 620, ISSN: 0004253375 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11826365B2 (en) | 2009-12-29 | 2023-11-28 | Dana-Farber Cancer Institute, Inc. | Type II raf kinase inhibitors |
JP2018515434A (ja) * | 2015-03-27 | 2018-06-14 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | サイクリン依存性キナーゼの阻害剤 |
US11325910B2 (en) | 2015-03-27 | 2022-05-10 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinases |
JP2021521129A (ja) * | 2018-04-11 | 2021-08-26 | キュリエント カンパニー, リミテッド | 薬学的に活性なピラゾロ−トリアジン誘導体および/またはピラゾロ−ピリミジン誘導体 |
JP7406501B2 (ja) | 2018-04-11 | 2023-12-27 | キュリエント カンパニー, リミテッド | 薬学的に活性なピラゾロ-トリアジン誘導体および/またはピラゾロ-ピリミジン誘導体 |
Also Published As
Publication number | Publication date |
---|---|
CA2978170A1 (en) | 2016-09-15 |
WO2016142855A2 (en) | 2016-09-15 |
JP6789962B2 (ja) | 2020-11-25 |
EP3268000B1 (en) | 2021-08-04 |
US11186576B2 (en) | 2021-11-30 |
CN107530329A (zh) | 2018-01-02 |
EP3268000A4 (en) | 2018-08-22 |
US20180258092A9 (en) | 2018-09-13 |
WO2016142855A3 (en) | 2016-11-03 |
US20180057497A1 (en) | 2018-03-01 |
CA2978170C (en) | 2024-02-27 |
CN107530329B (zh) | 2021-10-08 |
EP3268000A2 (en) | 2018-01-17 |
ES2899196T3 (es) | 2022-03-10 |
US20220281871A1 (en) | 2022-09-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6789962B2 (ja) | CDK阻害剤としてのピラゾロ[1,5−a][1,3,5]トリアジンとピラゾロ[1,5−a]ピリミジン誘導体 | |
TWI804003B (zh) | Tlr7/8拮抗劑及其用途 | |
EP3302448B1 (en) | Substituted heterocyclyl derivatives as cdk inhibitors | |
US7456164B2 (en) | 3- or 4-monosubtituted phenol and thiophenol derivatives useful as H3 ligands | |
ES2426407T3 (es) | Compuestos de pirrolo[2,3-d]pirimidina | |
EP3661934B1 (en) | [1,2,4]triazolo[4,3-a]pyridinyl substituted indole compounds | |
CA2944669A1 (en) | Inhibitors of cyclin-dependent kinase 7 (cdk7) | |
EA026201B1 (ru) | Циклобутилзамещенные производные пирролопиридина и пирролопиримидина как ингибиторы jak | |
KR20210049895A (ko) | 고 활성 sting 단백질 작용제 화합물 | |
JP2023521351A (ja) | がんの治療のためのent阻害剤としての大環状ジアミン誘導体、及びそれとアデノシン受容体拮抗薬との組合せ | |
EP3993802A1 (en) | Heterocyclic compounds as kinase inhibitors | |
WO2020247298A2 (en) | 1-pyrazolyl, 5-, 6- disubstituted indazole derivatives as lrrk2 inhibitors, pharmaceutical compositions, and uses thereof | |
JP2022505707A (ja) | 置換インドールおよびインダゾール化合物 | |
JP2018528197A (ja) | ヤヌスキナーゼ1選択的阻害剤及びその医薬用途 | |
JP2023540729A (ja) | 新規plk1分解誘導化合物 | |
WO2022150446A1 (en) | Tyk2 inhibitors | |
WO2024059808A1 (en) | Wee1 inhibitors and methods for treating cancer | |
WO2022130352A1 (en) | Novel compounds suitable for the treatment of dyslipidemia | |
EP4305040A1 (en) | Tricyclic pyridines as cyclin-dependent kinase 7 (cdk7) inhibitors | |
EP4081509A1 (en) | Novel compounds suitable for the treatment of dyslipidemia | |
CN117083272A (zh) | 调节nlrp3的4-烷氧基-6-氧代-哒嗪衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171129 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190304 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20191121 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191209 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20200309 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200413 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200709 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20201005 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20201104 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6789962 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |