JP2016513656A5 - - Google Patents
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- JP2016513656A5 JP2016513656A5 JP2016502156A JP2016502156A JP2016513656A5 JP 2016513656 A5 JP2016513656 A5 JP 2016513656A5 JP 2016502156 A JP2016502156 A JP 2016502156A JP 2016502156 A JP2016502156 A JP 2016502156A JP 2016513656 A5 JP2016513656 A5 JP 2016513656A5
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- heterocycle
- alkyl
- aryl
- cycloalkyl
- 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
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- 150000001875 compounds Chemical class 0.000 claims description 664
- 125000000623 heterocyclic group Chemical group 0.000 claims description 658
- 125000000217 alkyl group Chemical group 0.000 claims description 342
- 125000003118 aryl group Chemical group 0.000 claims description 335
- 229910052739 hydrogen Inorganic materials 0.000 claims description 316
- 239000001257 hydrogen Substances 0.000 claims description 316
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 309
- 150000002431 hydrogen Chemical class 0.000 claims description 290
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 279
- 125000003107 substituted aryl group Chemical group 0.000 claims description 271
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 270
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 239
- 229910052799 carbon Inorganic materials 0.000 claims description 157
- 150000002367 halogens Chemical class 0.000 claims description 153
- 229910052736 halogen Inorganic materials 0.000 claims description 152
- 125000003342 alkenyl group Chemical group 0.000 claims description 136
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 136
- 125000000304 alkynyl group Chemical group 0.000 claims description 135
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 133
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 129
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 129
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 107
- SQQWBSBBCSFQGC-JLHYYAGUSA-N ubiquinone-2 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CCC=C(C)C)=C(C)C1=O SQQWBSBBCSFQGC-JLHYYAGUSA-N 0.000 claims description 94
- 206010028980 Neoplasm Diseases 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 64
- 201000011510 cancer Diseases 0.000 claims description 63
- -1 pyridyl compound Chemical class 0.000 claims description 62
- 125000001424 substituent group Chemical group 0.000 claims description 52
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 51
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 50
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 44
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 32
- 102000001253 Protein Kinase Human genes 0.000 claims description 30
- 208000035475 disorder Diseases 0.000 claims description 30
- 108060006633 protein kinase Proteins 0.000 claims description 30
- 239000000651 prodrug Substances 0.000 claims description 29
- 229940002612 prodrug Drugs 0.000 claims description 29
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 28
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 210000000130 stem cell Anatomy 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 229910052698 phosphorus Inorganic materials 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 16
- 229930192474 thiophene Natural products 0.000 claims description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 13
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 13
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims description 9
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 9
- MJQSRSOTRPMVKB-UHFFFAOYSA-N 5h-imidazo[4,5-c]pyridazine Chemical compound C1=NNC2=NC=NC2=C1 MJQSRSOTRPMVKB-UHFFFAOYSA-N 0.000 claims description 9
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 9
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical compound C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 claims description 9
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 9
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 9
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 230000004083 survival effect Effects 0.000 claims description 8
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 7
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 7
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 claims description 7
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 150000003852 triazoles Chemical class 0.000 claims description 7
- 229910052720 vanadium Inorganic materials 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 6
- 230000035755 proliferation Effects 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 5
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 claims description 5
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 claims description 5
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 5
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 4
- 230000008685 targeting Effects 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 206010003571 Astrocytoma Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 3
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 208000017604 Hodgkin disease Diseases 0.000 claims description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 3
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 230000033115 angiogenesis Effects 0.000 claims description 3
- 125000003725 azepanyl group Chemical group 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 230000005754 cellular signaling Effects 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 230000003463 hyperproliferative effect Effects 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 125000003551 oxepanyl group Chemical group 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 3
- 210000000603 stem cell niche Anatomy 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 210000002536 stromal cell Anatomy 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 208000006542 von Hippel-Lindau disease Diseases 0.000 claims description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 208000008385 Urogenital Neoplasms Diseases 0.000 claims description 2
- 208000037964 urogenital cancer Diseases 0.000 claims description 2
- LMQPOBXTKNSKDQ-UHFFFAOYSA-N 1,3-benzothiazole 1H-indazole Chemical compound S1C=NC2=C1C=CC=C2.N2N=CC1=C2C=CC=C1 LMQPOBXTKNSKDQ-UHFFFAOYSA-N 0.000 claims 1
- 208000004575 Infectious Arthritis Diseases 0.000 claims 1
- 230000002458 infectious effect Effects 0.000 claims 1
- 201000001223 septic arthritis Diseases 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 description 98
- 229920000728 polyester Polymers 0.000 description 93
- 239000002904 solvent Substances 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
- 239000002253 acid Substances 0.000 description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- NFHFRUOZVGFOOS-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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 14
- 108091000080 Phosphotransferase Proteins 0.000 description 13
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- 239000003054 catalyst Substances 0.000 description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 9
- 150000008041 alkali metal carbonates Chemical class 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 125000003003 spiro group Chemical group 0.000 description 9
- 229910052723 transition metal Inorganic materials 0.000 description 9
- 150000003624 transition metals Chemical class 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 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 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
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- 201000010099 disease Diseases 0.000 description 7
- 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 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
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| JPWO2017026119A1 (ja) * | 2015-08-10 | 2018-05-24 | 大日本住友製薬株式会社 | 5−(チアゾール−4−イル)インドリン−2−オン誘導体の精製方法 |
| KR102109869B1 (ko) * | 2015-11-12 | 2020-05-13 | 영남대학교 산학협력단 | 7-아자인돌린-2-온 유도체 또는 이의 약제학적 허용가능한 염을 유효성분으로 함유하는 약학 조성물 |
| CN105461705B (zh) * | 2015-11-30 | 2018-04-10 | 中国医科大学 | 二苯并氮杂卓二酮类抗肿瘤化合物及其制备方法 |
| WO2018005444A2 (en) | 2016-06-28 | 2018-01-04 | Boston Biomedical, Inc. | Methods for treating cancer |
| CN107698593A (zh) * | 2016-08-09 | 2018-02-16 | 南京天印健华医药科技有限公司 | 作为fgfr抑制剂的杂环化合物 |
| CN106432228A (zh) * | 2016-09-06 | 2017-02-22 | 浙江司太立制药股份有限公司 | 含有4‑肟基‑1‑哌啶基片段的7‑氮杂吲哚啉‑2‑酮类化合物及其制备方法 |
| CN106397436A (zh) * | 2016-09-06 | 2017-02-15 | 浙江司太立制药股份有限公司 | 5‑溴‑7‑氮杂吲哚啉‑2‑酮类化合物及其制备方法 |
| WO2018098352A2 (en) | 2016-11-22 | 2018-05-31 | Jun Oishi | Targeting kras induced immune checkpoint expression |
| TWI779059B (zh) | 2017-06-30 | 2022-10-01 | 財團法人工業技術研究院 | 化合物用於製備治療自體免疫神經疾病及/或神經退化性疾病之藥物的用途 |
| CN110357878B (zh) * | 2018-03-26 | 2022-04-12 | 武汉誉祥医药科技有限公司 | 1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮衍生物及其医药用途 |
| CN119954787A (zh) | 2018-04-18 | 2025-05-09 | 星座制药公司 | 甲基修饰酶的调节剂、其组合物和用途 |
| US11919912B2 (en) | 2018-05-21 | 2024-03-05 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| BR112021005086A2 (pt) | 2018-09-18 | 2021-06-08 | 1Globe Biomedical Co., Ltd. | tratamento para doença hepática gordurosa não alcoólica |
| US12390460B2 (en) * | 2018-09-18 | 2025-08-19 | 1Globe Biomedical Co., Ltd. | Treatment for obesity |
| WO2021003339A1 (en) * | 2019-07-03 | 2021-01-07 | The Regents Of The University Of Colorado, A Body Corporate | Amp-activated protein kinase inhibitors and methods of making and using the same |
| US20230212120A1 (en) * | 2020-05-29 | 2023-07-06 | The Regents Of The University Of Michigan | Small molecule inhibitors of grk5 and grk5 subfamily members and uses thereof |
| CN111675647B (zh) * | 2020-06-26 | 2022-03-01 | 深圳技术大学 | 2-吲哚酮类pak1抑制剂及其在抗肿瘤治疗药物中的应用 |
| JP7713619B2 (ja) * | 2020-07-10 | 2025-07-28 | ブロッサムヒル・セラピューティクス・インコーポレイテッド | 大員環分子およびそれらの使用 |
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| CN114213396B (zh) * | 2022-01-27 | 2023-03-24 | 深圳市乐土生物医药有限公司 | 一种吲哚-2-酮类化合物及其制备方法与用途 |
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