CN117177968A - 对癌细胞生长表现出抑制作用的新型嘧啶衍生物 - Google Patents
对癌细胞生长表现出抑制作用的新型嘧啶衍生物 Download PDFInfo
- Publication number
- CN117177968A CN117177968A CN202280029605.6A CN202280029605A CN117177968A CN 117177968 A CN117177968 A CN 117177968A CN 202280029605 A CN202280029605 A CN 202280029605A CN 117177968 A CN117177968 A CN 117177968A
- Authority
- CN
- China
- Prior art keywords
- amino
- phenyl
- methyl
- pyrazol
- acrylamide
- 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.)
- Withdrawn
Links
- 230000010261 cell growth Effects 0.000 title description 8
- 150000003230 pyrimidines Chemical class 0.000 title description 6
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 4
- 230000001747 exhibiting effect Effects 0.000 title description 3
- 230000002700 inhibitory effect on cancer Effects 0.000 title description 2
- -1 pyrimidine derivative compounds Chemical class 0.000 claims abstract description 111
- 150000001875 compounds Chemical class 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 239000012453 solvate Substances 0.000 claims description 28
- 238000003780 insertion Methods 0.000 claims description 26
- 230000037431 insertion Effects 0.000 claims description 26
- MJBWDEQAUQTVKK-IAGOWNOFSA-N aflatoxin M1 Chemical compound C=1([C@]2(O)C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O MJBWDEQAUQTVKK-IAGOWNOFSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 208000020816 lung neoplasm Diseases 0.000 claims description 12
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 11
- 201000005202 lung cancer Diseases 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 9
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- ATAWWMJFQZUDPF-IBGZPJMESA-N CN(C)[C@@H](CC1)CN1C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O Chemical compound CN(C)[C@@H](CC1)CN1C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O ATAWWMJFQZUDPF-IBGZPJMESA-N 0.000 claims description 3
- ATAWWMJFQZUDPF-LJQANCHMSA-N CN(C)[C@H](CC1)CN1C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O Chemical compound CN(C)[C@H](CC1)CN1C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O ATAWWMJFQZUDPF-LJQANCHMSA-N 0.000 claims description 3
- OOWYZHZGLYINOX-IBGZPJMESA-N CN([C@@H]1CN(C)CC1)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O Chemical compound CN([C@@H]1CN(C)CC1)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O OOWYZHZGLYINOX-IBGZPJMESA-N 0.000 claims description 3
- OOWYZHZGLYINOX-LJQANCHMSA-N CN([C@H]1CN(C)CC1)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O Chemical compound CN([C@H]1CN(C)CC1)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O OOWYZHZGLYINOX-LJQANCHMSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005265 dialkylamine group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 150000002367 halogens Chemical class 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
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- FXRNAKPDQHKAGQ-QFIPXVFZSA-N CC(C)OC(C1=CN=C(NC(C=C(C(N(C)[C@@H]2CN(C)CC2)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O Chemical compound CC(C)OC(C1=CN=C(NC(C=C(C(N(C)[C@@H]2CN(C)CC2)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O FXRNAKPDQHKAGQ-QFIPXVFZSA-N 0.000 claims description 2
- FXRNAKPDQHKAGQ-JOCHJYFZSA-N CC(C)OC(C1=CN=C(NC(C=C(C(N(C)[C@H]2CN(C)CC2)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O Chemical compound CC(C)OC(C1=CN=C(NC(C=C(C(N(C)[C@H]2CN(C)CC2)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O FXRNAKPDQHKAGQ-JOCHJYFZSA-N 0.000 claims description 2
- SKQVSCJSSVYMFK-JOCHJYFZSA-N CC(C)OC(C1=CN=C(NC(C=C(C(N(CC2)C[C@@H]2N(C)C)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O Chemical compound CC(C)OC(C1=CN=C(NC(C=C(C(N(CC2)C[C@@H]2N(C)C)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O SKQVSCJSSVYMFK-JOCHJYFZSA-N 0.000 claims description 2
- SKQVSCJSSVYMFK-QFIPXVFZSA-N CC(C)OC(C1=CN=C(NC(C=C(C(N(CC2)C[C@H]2N(C)C)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O Chemical compound CC(C)OC(C1=CN=C(NC(C=C(C(N(CC2)C[C@H]2N(C)C)=C2)NC(C=C)=O)=C2OC)N=C1NC(C=CC=C1)=C1C1=NN(C)C=C1)=O SKQVSCJSSVYMFK-QFIPXVFZSA-N 0.000 claims description 2
- XMKVXQFALBSAEE-UHFFFAOYSA-N CN(C)CCN(C)C(C=C(C(NC1=NC=NC(NC(C=CC=C2)=C2N2N=CC=C2)=C1)=C1)OC)=C1NC(C=C)=O Chemical compound CN(C)CCN(C)C(C=C(C(NC1=NC=NC(NC(C=CC=C2)=C2N2N=CC=C2)=C1)=C1)OC)=C1NC(C=C)=O XMKVXQFALBSAEE-UHFFFAOYSA-N 0.000 claims description 2
- DKSWTBYYEIJHCP-UHFFFAOYSA-N CN(C=C1)N=C1C(C=CC=C1)=C1NC1=NC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCN(C)CC2)=NC=C1Cl Chemical compound CN(C=C1)N=C1C(C=CC=C1)=C1NC1=NC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCN(C)CC2)=NC=C1Cl DKSWTBYYEIJHCP-UHFFFAOYSA-N 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 2
- 208000009905 Neurofibromatoses 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
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 206010027191 meningioma Diseases 0.000 claims description 2
- 201000004931 neurofibromatosis Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 8
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 8
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 8
- 208000008334 Dermatofibrosarcoma Diseases 0.000 claims 1
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 claims 1
- 102000001301 EGF receptor Human genes 0.000 description 46
- 108060006698 EGF receptor Proteins 0.000 description 46
- 238000002360 preparation method Methods 0.000 description 45
- 239000007787 solid Substances 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 238000002474 experimental method Methods 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 230000035772 mutation Effects 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000003814 drug Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- UIYKQBXRFZCXFX-UHFFFAOYSA-N 2-pyrazol-1-ylaniline Chemical compound NC1=CC=CC=C1N1N=CC=C1 UIYKQBXRFZCXFX-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 150000001448 anilines Chemical class 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229960001433 erlotinib Drugs 0.000 description 4
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229960002584 gefitinib Drugs 0.000 description 4
- 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 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CZGIEJXGCLWRPY-ZCFIWIBFSA-N (3r)-n,1-dimethylpyrrolidin-3-amine Chemical compound CN[C@@H]1CCN(C)C1 CZGIEJXGCLWRPY-ZCFIWIBFSA-N 0.000 description 3
- AVAWMINJNRAQFS-ZCFIWIBFSA-N (3r)-n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)[C@@H]1CCNC1 AVAWMINJNRAQFS-ZCFIWIBFSA-N 0.000 description 3
- CZGIEJXGCLWRPY-LURJTMIESA-N (3s)-n,1-dimethylpyrrolidin-3-amine Chemical compound CN[C@H]1CCN(C)C1 CZGIEJXGCLWRPY-LURJTMIESA-N 0.000 description 3
- AVAWMINJNRAQFS-LURJTMIESA-N (3s)-n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)[C@H]1CCNC1 AVAWMINJNRAQFS-LURJTMIESA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 3
- 229960001686 afatinib Drugs 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 230000005907 cancer growth Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- RRTHCTNQZMBRJU-UHFFFAOYSA-N CC1=CN=C(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N(C)CCN(C)C)N=C1NC(C=CC=C1)=C1N1N=CC=C1 Chemical compound CC1=CN=C(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N(C)CCN(C)C)N=C1NC(C=CC=C1)=C1N1N=CC=C1 RRTHCTNQZMBRJU-UHFFFAOYSA-N 0.000 description 2
- HKMIOSJBPMHFSU-UHFFFAOYSA-N CN(C)CCN(C)C(C([N+]([O-])=O)=C1)=CC(OC)=C1NC1=NC=NC(NC(C=CC=C2)=C2C2=NN(C)C=C2)=C1 Chemical compound CN(C)CCN(C)C(C([N+]([O-])=O)=C1)=CC(OC)=C1NC1=NC=NC(NC(C=CC=C2)=C2C2=NN(C)C=C2)=C1 HKMIOSJBPMHFSU-UHFFFAOYSA-N 0.000 description 2
- MVHRUSGNNLMQFX-UHFFFAOYSA-N CN(C=C1)N=C1C(C=CC=C1)=C1NC1=CC(NC(C=C(C(F)=C2)[N+]([O-])=O)=C2OC)=NC=N1 Chemical compound CN(C=C1)N=C1C(C=CC=C1)=C1NC1=CC(NC(C=C(C(F)=C2)[N+]([O-])=O)=C2OC)=NC=N1 MVHRUSGNNLMQFX-UHFFFAOYSA-N 0.000 description 2
- RLZNQMCOYIEHPN-UHFFFAOYSA-N COC(C=C(C([N+]([O-])=O)=C1)F)=C1NC1=CC(NC(C=CC=C2)=C2N2N=CC=C2)=NC=N1 Chemical compound COC(C=C(C([N+]([O-])=O)=C1)F)=C1NC1=CC(NC(C=CC=C2)=C2N2N=CC=C2)=NC=N1 RLZNQMCOYIEHPN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- SRJBDGLSCPDXBL-UHFFFAOYSA-N ethyl 2,4-dichloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1Cl SRJBDGLSCPDXBL-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229950007440 icotinib Drugs 0.000 description 2
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 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
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- FNNAWVXVOHNOFF-UHFFFAOYSA-N methyl 2,4-dichloropyrimidine-5-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)N=C1Cl FNNAWVXVOHNOFF-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- LPFWVDIFUFFKJU-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one Chemical compound C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F LPFWVDIFUFFKJU-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 1
- DQXNTSXKIUZJJS-UHFFFAOYSA-N 2,4-dichloro-5-methylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1Cl DQXNTSXKIUZJJS-UHFFFAOYSA-N 0.000 description 1
- KMHSUNDEGHRBNV-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carbonitrile Chemical compound ClC1=NC=C(C#N)C(Cl)=N1 KMHSUNDEGHRBNV-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- DFXYQHYLJVQMNV-UHFFFAOYSA-N 2-cyclopropyloxy-4-fluoro-5-nitroaniline Chemical compound FC1=CC(=C(N)C=C1[N+](=O)[O-])OC1CC1 DFXYQHYLJVQMNV-UHFFFAOYSA-N 0.000 description 1
- FWTPYXROUXJRBF-UHFFFAOYSA-N 2-ethoxy-4-fluoro-5-nitroaniline Chemical compound C(C)OC1=C(N)C=C(C(=C1)F)[N+](=O)[O-] FWTPYXROUXJRBF-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- HQQVXVKQOPZRBJ-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-furo[3,4-c]pyrrole Chemical compound C1OCC2CNCC21 HQQVXVKQOPZRBJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MNILDQSRDHCFJG-UHFFFAOYSA-N 3-oxa-8-azabicyclo[3.2.1]octane Chemical compound C1OCC2CCC1N2 MNILDQSRDHCFJG-UHFFFAOYSA-N 0.000 description 1
- GSPVBDHZWTYEPF-UHFFFAOYSA-N 4-fluoro-5-nitro-2-propan-2-yloxyaniline Chemical compound FC1=CC(=C(N)C=C1[N+](=O)[O-])OC(C)C GSPVBDHZWTYEPF-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 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
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 239000005740 Boscalid Substances 0.000 description 1
- FHSQIIOGAZUPNK-UHFFFAOYSA-N CC(C)OC(C(NC1=NC=NC(NC(C=CC=C2)=C2C2=NN(C)C=C2)=C1)=C1)=CC(N(C)CCN(C)C)=C1NC(C=C)=O Chemical compound CC(C)OC(C(NC1=NC=NC(NC(C=CC=C2)=C2C2=NN(C)C=C2)=C1)=C1)=CC(N(C)CCN(C)C)=C1NC(C=C)=O FHSQIIOGAZUPNK-UHFFFAOYSA-N 0.000 description 1
- VFCORMFCJAMJNZ-UHFFFAOYSA-N CCN(CC)CCN(C)C(C=C(C(NC1=NC=NC(NC(C=CC=C2)=C2N2N=CC=C2)=C1)=C1)OC)=C1NC(C=C)=O Chemical compound CCN(CC)CCN(C)C(C=C(C(NC1=NC=NC(NC(C=CC=C2)=C2N2N=CC=C2)=C1)=C1)OC)=C1NC(C=C)=O VFCORMFCJAMJNZ-UHFFFAOYSA-N 0.000 description 1
- KVWUWFFNMICLBG-UHFFFAOYSA-N CN(C)CCN(C)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1C#N)=C1)OC)=C1NC(C=C)=O Chemical compound CN(C)CCN(C)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1C#N)=C1)OC)=C1NC(C=C)=O KVWUWFFNMICLBG-UHFFFAOYSA-N 0.000 description 1
- HLVAWCMMCGCOHF-UHFFFAOYSA-N CN(C)CCN(C)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O Chemical compound CN(C)CCN(C)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2C2=NN(C)C=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O HLVAWCMMCGCOHF-UHFFFAOYSA-N 0.000 description 1
- VQTYPXJPBZYXDY-UHFFFAOYSA-N CN(C)CCN(C)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2N2N=CC=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O Chemical compound CN(C)CCN(C)C(C=C(C(NC(N=C1NC(C=CC=C2)=C2N2N=CC=C2)=NC=C1Cl)=C1)OC)=C1NC(C=C)=O VQTYPXJPBZYXDY-UHFFFAOYSA-N 0.000 description 1
- ZCMSJWPKFHMGNC-UHFFFAOYSA-N CN(C)CCN(C)C(C=C(C(NC1=NC=NC(NC(C=CC=C2)=C2C2=NN(C)C=C2)=C1)=C1)OC2CC2)=C1NC(C=C)=O Chemical compound CN(C)CCN(C)C(C=C(C(NC1=NC=NC(NC(C=CC=C2)=C2C2=NN(C)C=C2)=C1)=C1)OC2CC2)=C1NC(C=C)=O ZCMSJWPKFHMGNC-UHFFFAOYSA-N 0.000 description 1
- JUKQEQCBILQJGR-UHFFFAOYSA-N CN(C=C1)N=C1C(C=CC=C1)=C1NC1=CC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCN(C)CC2)=NC=N1 Chemical compound CN(C=C1)N=C1C(C=CC=C1)=C1NC1=CC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCN(C)CC2)=NC=N1 JUKQEQCBILQJGR-UHFFFAOYSA-N 0.000 description 1
- UCSPQVZZJWEYMZ-UHFFFAOYSA-N CN(C=C1)N=C1C(C=CC=C1)=C1NC1=CC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCOCC2)=NC=N1 Chemical compound CN(C=C1)N=C1C(C=CC=C1)=C1NC1=CC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCOCC2)=NC=N1 UCSPQVZZJWEYMZ-UHFFFAOYSA-N 0.000 description 1
- LEJTYROGSLALEU-UHFFFAOYSA-N CN(C=C1)N=C1C(C=CC=C1)=C1NC1=NC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCOCC2)=NC=C1Cl Chemical compound CN(C=C1)N=C1C(C=CC=C1)=C1NC1=NC(NC(C(OC)=C2)=CC(NC(C=C)=O)=C2N2CCOCC2)=NC=C1Cl LEJTYROGSLALEU-UHFFFAOYSA-N 0.000 description 1
- QNPSDCFBJFSVTN-UHFFFAOYSA-N CN(C=C1)N=C1C(C=CC=C1)=C1NC1=NC=NC(Cl)=C1 Chemical compound CN(C=C1)N=C1C(C=CC=C1)=C1NC1=NC=NC(Cl)=C1 QNPSDCFBJFSVTN-UHFFFAOYSA-N 0.000 description 1
- ZSZNVEOSPQZIFN-UHFFFAOYSA-N COC(C(NC1=NC=NC(NC(C=CC=C2)=C2N2N=CC=C2)=C1)=C1)=CC(N2C3COCC2CC3)=C1NC(C=C)=O Chemical compound COC(C(NC1=NC=NC(NC(C=CC=C2)=C2N2N=CC=C2)=C1)=C1)=CC(N2C3COCC2CC3)=C1NC(C=C)=O ZSZNVEOSPQZIFN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- YTHQLSALECZPNM-UHFFFAOYSA-N ClC1=CC(NC(C=CC=C2)=C2N2N=CC=C2)=NC=N1 Chemical compound ClC1=CC(NC(C=CC=C2)=C2N2N=CC=C2)=NC=N1 YTHQLSALECZPNM-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- UULXEAMJOUJTGD-UHFFFAOYSA-N O=C(C(C(Cl)=N1)=CN=C1Cl)OC1CC1 Chemical compound O=C(C(C(Cl)=N1)=CN=C1Cl)OC1CC1 UULXEAMJOUJTGD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 1
- 229940118790 boscalid Drugs 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
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000009134 cell regulation 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000011534 incubation Methods 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
- 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
- 230000002147 killing effect Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229960003511 macrogol Drugs 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
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940015637 mobocertinib Drugs 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000011518 platinum-based chemotherapy Methods 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229950009876 poziotinib Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- YRJUHXRUVTWBKE-UHFFFAOYSA-N propan-2-yl 2,4-dichloropyrimidine-5-carboxylate Chemical compound CC(C)OC(=O)C1=CN=C(Cl)N=C1Cl YRJUHXRUVTWBKE-UHFFFAOYSA-N 0.000 description 1
- AZSRSNUQCUDCGG-UHFFFAOYSA-N propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C(=CC(=C(C=1)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)C(=O)OC(C)C)OC)N(C)CCN(C)C AZSRSNUQCUDCGG-UHFFFAOYSA-N 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000011571 secondary malignant neoplasm Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及新型嘧啶衍生化合物。
Description
技术领域
本发明涉及对癌细胞的生长具有优异的抑制作用的新型嘧啶衍生物,其制备方法以及包含其的药物组合物。
背景技术
EGFR是一种跨膜蛋白,其是表皮生长因子(EGF)的受体并且是通过与胞外EGF结合并向细胞传递信号从而在细胞调节中起到重要作用的酪氨酸激酶。EGFR有4种类型:EGFR1(erbB-1)、HER2/neu(ErbB-2)、HER3(ErbB-3)和HER4(ErbB-4)。已知的是,影响各个EGFR的表达或活性的突变导致细胞分裂异常,从而影响癌症发展或癌症进展。
在肺癌、成胶质细胞瘤和头颈癌中观察到导致EGFR过度表达或过度活性(持续活性)的EGFR突变,并且在所有上皮癌中超过30%观察到EGFR突变。特别地,在超过50%的非小细胞肺癌中观察到表皮生长因子受体(EGFR)突变,而非小细胞肺癌占包括韩国在内的亚洲人中肺癌的80%~85%。
已经开发了多种作为小分子治疗剂的物质用于抑制已激活的EGFR的活性。特别地,作为肺癌药物,已经开发了吉非替尼(Gefitinib)、厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、布格替尼(Brigatinib)、埃克替尼(Icotinib)、奥希替尼(Osimertinib)、拉泽替尼(Lazertinib)等,并且作为结直肠癌药物,已经开发了西妥昔单抗(Cetuximab),这是一种单克隆抗体。
主要在非小细胞肺癌中发现的突变为外显子19缺失、L858R和外显子20插入。特别地,外显子20插入占非小细胞肺癌中发现的所有EGFR突变的4~10%。对于外显子19缺失和L858R突变(其是最常见的EGFR突变),例如吉非替尼和厄洛替尼等小分子EGFR激酶抑制剂被用作治疗剂。然而,EGFR外显子20插入突变不仅对现有的酪氨酸激酶抑制剂(吉非替尼、厄洛替尼、阿法替尼)无效,而且对针对EGFR T790m的靶向剂奥希替尼和拉泽替尼也无响应,因此难以进行靶向治疗。
近来,美国食品和药品管理局(FDA)指定莫博替尼(mobocertinib)作为用于治疗具有EGFR外显子20插入的转移性非小细胞肺癌的患者的新型治疗剂,这些患者在接受铂类化疗过程中或之后病情出现进展。当前,正在进行使用多种EGFR抑制剂作为治疗剂的肺癌临床研究,但是没有作为用于治疗具有表皮生长因子受体外显子20插入突变的肺癌的标准疗法而被批准的药物,因此迫切需要开发能够治疗这种疾病的药物。
因此,本发明人研究了靶向EGFR外显子20插入突变体的EGFR抑制剂。由此,通过确认本发明的新型嘧啶衍生化合物针对EGFR外显子20插入突变体具有优异的抑制活性并且能够用于治疗与EGFR突变相关的癌症,从而完成本发明。
现有技术文献
(非专利文献1)Annals of Oncology 29(Supplement 1):i3-i9,2018。
(非专利文献2)Transl Lung Cancer Res 2019;8(3):302-316。
发明内容
技术问题
本发明的一个实例提供了一种选择性地抑制由EGFR外显子20突变体导致的癌细胞的生长和耐药性或具有这种耐药性的癌症而几乎没有副作用的新型嘧啶衍生化合物。
本发明的一个实例提供了包含所述新型嘧啶衍生化合物并且通过抑制癌细胞生长从而具有抗肿瘤活性的药物组合物。
本发明的一个实例提供了通过向受试者施用新型嘧啶衍生化合物从而治疗EGFR外显子20插入突变体导致的疾病的方法。
本发明的一个实例提供了新型嘧啶衍生化合物用于制备预防或治疗与EGFR外显子20插入突变体相关的疾病的药物组合物的用途。
本发明的一个实例提供了制备所述嘧啶衍生化合物的方法。
技术方案
为了实现以上目标,本发明提供了新型嘧啶衍生物即式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐:
<式I>
其中,
A、B和E各自独立地为N或C原子,
D为N或C,
X为C、N或O,
Y为C、N或O,
L为单键或NR5,R5为H或C1至C4烷基,
Z1和Z2各自独立地为C1至C4烷基,或者各自独立地包含碳并且相互连接,从而与X和Y形成5元至8元环,
Z3为(CH2)n,或者包含碳并且与Z1、Z2、X和Y形成5元至8元环,n为1至3的整数,
R1为H、吡唑或被C1至C4烷基取代的吡唑,
R2为H、卤素、C1至C4烷基、C1至C5烷基酯(例如,C2至C5烷基酯)、CN或被卤素取代的C1至C4烷基(然而,如果D为N,则R2不存在),
R3为H、C1至C5直链或支链烷基、被卤素取代的C1至C5烷基,或C3至C5环烷基,并且
R4不存在,或为H、C1至C4烷基、C1至C4单烷基或C1至C4二烷基胺。
本发明提供了式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐,用于治疗过表达外显子20插入突变EGFR导致的疾病。
本发明提供了用于治疗过表达EGFR外显子20插入突变基因或蛋白的疾病的药物组合物,其包含作为活性成分的式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐,以及可接受的载体。
本发明提供了用于治疗过表达EGFR外显子20插入突变基因或蛋白的疾病的方法,其包括向需要治疗的受试者施用有效量的式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐。
本发明提供了式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐在制备用于预防或治疗过表达EGFR外显子20插入突变基因或蛋白的疾病的药物组合物的用途。
有益效果
所述新型嘧啶衍生化合物能够抑制表达EGFR外显子20插入突变基因或蛋白的癌细胞的生长。
因此,本发明的新型嘧啶衍生化合物能够用于治疗EGFR外显子20插入突变导致的癌症。
具体实施方式
在下文中,将详细描述本发明的实施方式。然而,这是作为实例提供的,并且本发明并不局限于此,并且本发明仅由以下描述的权利要求的范围来定义。此外,即使是实施本发明所必需的配置,也将省略对本领域技术人员从已知技术能够清楚地实施的配置的详细描述。
除非以下另有说明,否则本发明的术语“化合物”、“式I的化合物”、“式I表示的化合物”或“式I的嘧啶衍生化合物”是指化合物自身、其溶剂化物、立体异构体和盐。
在此,术语“直链或支链烷基”表示直链、支链单价饱和烃基。除非另有定义,否则所述烷基包含1至5个、1至4个或1至3个碳原子。所述烷基的实例包括甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如,正丁基、异丁基和叔丁基)、戊基(例如,正戊基、异戊基和新戊基)。在此,所述烷基可以可选地部分不饱和,从而可以为以下的烯基或炔基。另外,所述烷基可以进一步被其他取代基取代。
在此,术语“烷氧基”可以为直链、支链或环链。烷氧基的碳原子数没有特别限制,但可以为,例如,1至5个碳原子。具体地,其可以为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、新戊氧基、异戊氧基等,但不限于此。
在此,术语“卤代烷基”或“被卤素取代的烷基”是指具有一个以上的卤素取代基的烷基。卤代烷基包括-CF3、-C2F5、-CHF2、-CCl3、-CHCl2和-C2Cl。除非另有定义,否则卤代烷基通常包含1至6个、1至5个、1至4个或1至3个碳原子,并且可以进一步被其他取代基取代。
在此,术语“环烷基”是指包含环化的烷基、烯基和炔基在内的非芳香族碳环、环烷基可以包含单环或多环。所述多环具有例如2、3或4个稠合的环。除非另有定义,环烷基通常含有3至5个环碳原子。环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环己二烯基、环庚二烯基等,并且可以进一步被其他取代基取代。
本发明提供了以下式I表示的嘧啶衍生化合物、溶剂化物、立体异构体或药学上可接受的盐:
<式I>
其中,
A、B和E各自独立地为N或CH,
D为N或C,
X为C、N或O,
Y为C、N或O,
L为单键或NR5,R5为H或C1至C4烷基,
Z1和Z2各自独立地为C1至C4烷基,或者各自独立地包含碳并且相互连接,从而与X和Y形成5元至8元环,
Z3为(CH2)n,或者包含碳并且与Z1、Z2、X和Y形成5元至8元环,n为1至3的整数,
R1为H、吡唑或被C1至C4烷基取代的吡唑,
R2为H、卤素、C1至C4烷基、C1至C4烷基酯、CN或被卤素取代的C1至C4烷基(然而,如果D为N,则R2不存在),
R3为H、C1至C5直链或支链烷基、被卤素取代的C1至C5烷基,或C3至C5环烷基,并且
R4不存在,或为H、C1至C4烷基、C1至C4单烷基或C1至C4二烷基胺。
例如,在以上式I中,A和D可以为N。
例如,在以上式I中,A和E可以为N。
例如,在以上式I中,Z1和Z2可以各自独立地包含碳并且可以相互连接,从而与X和Y形成5元至8元的单环、稠合双环或桥连双环。此时,在式I中,Z3可以包含碳原子并且与Z1、Z2、X和Y形成5元至8元环,并且可以为杂环。所述杂环可以包含选自由O、S、N和P组成的组中的一种以上的杂原子。例如,所述杂环可以包括选自由O和N组成的组中的一种以上的杂原子。例如,所述杂环可以包含1至2个杂原子。
例如,在式I中,当L为单键时,X可以为N或O。
例如,在式I中,当L为单键时,X可以为N。
例如,在式I中,当L为NR5时,X可以为CH。
例如,在式I中,当Y为O时,R4可以不存在。
例如,式I的化合物可以为以下化合物中的任一种:
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-异丙氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺;
N-(4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-吗啉基苯基)丙烯酰胺;
(S)-N-(2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
(R)-N-(2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
(R)-N-(4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
(S)-N-(4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-4-(2,2,2-三氟乙氧基)苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-乙氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;
N-(4-环丙氧基-2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(5-((5-氰基-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)丙烯酰胺;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸异丙酯;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸甲酯;
4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸甲酯;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸乙酯;
4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸乙酯;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸环丙酯;
2-((5-丙烯酰氨基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
2-((5-丙烯酰氨基-2-甲氧基-4-吗啉基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(S)-2-((5-丙烯酰氨基-4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(R)-2-((5-丙烯酰氨基-4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(R)-2-((5-丙烯酰氨基-2-甲氧基-4-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(S)-2-((5-丙烯酰氨基-2-甲氧基-4-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)-5-氯嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺;
N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-吗啉基苯基)丙烯酰胺;
(S)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺;
(R)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺;
(R)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)丙烯酰胺;
(S)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)丙烯酰胺;
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二乙基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-4-甲氧基-2-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)苯基)丙烯酰胺;以及
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-甲氧基苯基)丙烯酰胺。
根据本发明的一个实施方式,式I的化合物抑制EGFR外显子20插入突变肺癌细胞系的生长,并且诱导凋亡。具体地,本发明的实施例中的化合物的IC50值为25nM以下,30nM以下、35nM以下、40nM以下、45nM以下、50nM以下、500nM以下或1000nM以下。
此外,根据本发明的一个实施方式,式I的化合物比莫博替尼更有效,莫博替尼是对照药物,曾被开发为用于治疗具有EGFR外显子20插入突变体的癌症患者的抗癌药物,并且式I的化合物具有与波奇替尼(poziotinib)等同的活性,而波奇替尼有毒性问题。
总之,根据本发明的一个实施方式,式I的化合物能够用作治疗具有EGFR外显子20插入突变体的癌症的药物组合物,即,用作抗癌剂。
此外,根据本发明的一个实施方式,式I的化合物不仅可以抑制EGFR外显子20插入,还可以抑制其他EGFR亚型。
癌症可以选自由肝癌、肝细胞癌、胃肠道癌、胃癌、与神经纤维瘤病相关的脑膜瘤、胰腺癌、白血病、骨髓增殖性疾病、骨髓增生异常疾病、皮肤纤维肉瘤、乳腺癌、肺癌、甲状腺癌、结直肠癌、前列腺癌、卵巢癌、脑肿瘤、头颈癌和成胶质细胞瘤组成的组。另外,肺癌可以为非小细胞肺癌。此外,癌症可以为由上述各种癌症转移至其他器官的继发性癌症。
根据本发明的一个实施方式,所述化合物可以是其药学上可接受的盐的形式。所述盐是指通常用于本发明所属的制药行业的盐。例如,所述盐能够以由选自由以下的酸组成的组中的至少一种酸诱导生成的盐的形式使用:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸等,并且本发明中所指的盐的种类不限于所列举的盐。
根据本发明的一个实施方式,所述化合物可以是其溶剂化物的形式。所述“溶剂化物”表示由一个以上的溶质分子(即式I的化合物或其药学上可接受的盐)和一个以上的溶剂分子形成的复合物或聚集物。溶剂化物可能是与例如水、甲醇、乙醇、异丙醇或乙酸等多种溶剂分子形成的复合物或聚集物。
根据本发明的一个实施方式,所述化合物可以是其立体异构体的形式。所述立体异构体包括例如对映异构体和非对映异构体等所有立体异构体。所述化合物可以为立体异构纯形式或一种以上的立体异构体的混合物,例如外消旋混合物。特定立体异构体的分离能够通过本领域中已知的常规方法中的一种来进行。在本发明的化合物的一些实施方式中,特定的立体异构体的抗癌作用可能大于外消旋混合物的抗癌效果。在此情况下,通过使用特定的立体异构体能够减少剂量。因此,通过分离对癌细胞具有高杀伤作用的特定的立体异构体(例如对映异构体或非对映异构体),能够有效地治疗癌症。
本发明的另一个方面提供了药物组合物,所述药物组合物包含治疗有效量的如上所述的式I的化合物,或其药学上可接受的盐或溶剂化物或立体异构体,以及药学上可接受的载体。
在本发明的组合物中,所述化合物,或其药学上可接受的盐或溶剂化物或立体异构体如下文所述。
在本发明的组合物中,“药学上可接受的载体”是指与活性成分组合使用的物质,通常为惰性物质,有助于活性成分的应用。所述载体包括常规的药学上可接受的赋形剂、添加剂或稀释剂。所述载体可以包括,例如,选自填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧化剂、润滑剂、调味剂、增稠剂、着色剂、乳化剂、悬浮剂、稳定剂、pH调节剂和等渗剂中的至少一种。
其可以选自由以下成分组成的组:微晶纤维素、一水乳糖、无水乳糖、乳糖、淀粉、甘露醇、羧甲基纤维素、山梨糖醇及其组合,但不限于此。粘合剂可以选自由以下成分组成的组:羟丙基纤维素、羟丙基甲基纤维素、羟丙甲纤维素、聚乙烯基乙酸、聚维酮、聚乙烯吡咯烷酮、共聚维酮、聚乙二醇(macrogol)、十二烷基磺酸钠、轻质无水硅酸、合成硅酸铝、硅酸钙或例如偏硅酸铝镁等硅酸盐衍生物、例如磷酸氢钙等磷酸盐、例如碳酸钙等碳酸盐、预胶化淀粉、例如阿拉伯胶等胶类、明胶、例如乙基纤维素等纤维素衍生物,及其混合物,但不限于此。
崩解剂可以选自由以下成分组成的组:低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、淀粉乙醇酸钠、F-melt,及其组合,但不限于此。助流剂可以选自由胶体二氧化硅、水合二氧化硅及其组合组成的组,但不限于此。
润滑剂可以选自由硬脂酸镁、二氧化硅、滑石、轻质无水硅酸、硬脂富马酸钠及其组合组成的组,但不限于此。
pH调节剂可以为酸化剂,例如乙酸、抗坏血酸、苹果酸、琥珀酸、酒石酸、富马酸和柠檬酸,以及碱化剂,例如沉淀碳酸钙、氨水、葡甲胺、碳酸钠、氧化镁、碳酸镁、柠檬酸钠和磷酸三钙。
抗氧化剂可以为二丁基羟基甲苯、丁基羟基苯甲醚、生育酚乙酸酯、生育酚、没食子酸丙酯、亚硫酸氢钠和焦亚硫酸钠。增溶剂可以为聚氧乙烯山梨醇脂肪酸酯,例如十二烷基硫酸钠和聚山梨醇酯、多库酯钠和泊洛沙姆。
此外,可以使用选自着色剂和调味剂的药学上可接受的添加剂作为各种添加剂来配制本发明的制剂。
在本发明中,添加剂的范围不限于上述添加剂的使用,并且能够通过选择上述添加剂并在通常剂量范围内包含上述添加剂来进行配制。
根据本发明的一个实施方式,所述药物组合物以口服制剂的形式根据常规方法配制并使用,例如粉末剂、颗粒剂、片剂、胶囊剂、混悬剂、乳剂、糖浆剂和气雾剂、外用制剂、栓剂或无菌注射液。
根据本发明的一个实施方式,所述组合物可以口服施用或胃肠外施用,胃肠道外施用包括静脉、腹腔、皮下、直肠和局部施用。
本发明的另一个方面提供了治疗受试者的疾病的方法,所述方法包括向受试者施用治疗有效量的式I的化合物,或其药学上可接受的盐或溶剂化物或立体异构体。
在上述方法中,本领域技术人员能够根据患者的情况适当地选择施用途径。施用可以是口服或胃肠外施用。胃肠外施用包括静脉、腹腔、皮下、直肠和局部施用。
在上述方法中,可以根据例如患者情况、施用途径、主治医师的判断等如上所述的各种因素而对剂量进行各种改变。有效剂量能够从体外或动物模型试验得到的剂量-响应曲线中进行估算。本发明的化合物在待施用的组合物中存在的比例和浓度可以根据化学特性、施用途径、治疗剂量等来确定。能够向个体施用的有效剂量约为1g/kg/天,或约0.1g/kg/天至约500mg/kg/天。剂量可以根据受试者的年龄、体重、敏感性或症状进行改变。
另外,包含作为活性成分的本发明的式I的化合物或其溶剂化物、立体异构体或药学上可接受的盐的药物组合物能够用于预防或治疗表达EGFR外显子20插入突变基因或蛋白的癌症的方法中,所述方法包括向有需要的受试者施用所述组合物的步骤。
根据本发明的一个实施方式,所述药物组合物以口服制剂的形式根据常规方法配制并使用,例如粉末剂、颗粒剂、片剂、胶囊剂、混悬剂、乳剂、糖浆剂和气雾剂、外用制剂、栓剂或无菌注射液。
在本发明的一个方面,活性成分的含量范围可以占用于预防、改善或治疗表达EGFR外显子20插入突变基因或蛋白的癌症的药物组合物总重量的0.00001至100重量%、0.0001至95重量%或0.001至90重量%。
在根据本发明的一个实施方式的药物组合物中,式I表示的化合物或其药学上可接受的盐的剂量可以根据患者的年龄、体重、症状、施用途径等适当地进行改变。
本发明的式I表示的化合物或其药学上可接受的盐的剂量可以为0.00001mg/kg/天至2000mg/kg/天、0.0001mg/kg/天至1000mg/kg/天、0.001mg/kg/天至800mg/kg/天、0.001mg/kg/天至500mg/kg/天、0.001mg/kg/天至100mg/kg/天、0.001mg/kg/天至80mg/kg/天,或0.01mg/kg/天至70mg/kg/天
本发明的式I表示的嘧啶衍生物或其药学上可接受的盐的含量可以为每单位剂形0.00001至100重量%、0.0001至95重量%、0.0001至90重量%、0.001至70重量%,或0.001至50重量%
本发明的式I表示的化合物或其药学上可接受的盐的剂量浓度可以为0.0001至500μM、0.001至300μM、0.001至150μM、0.001至130μM、0.001至100μM、0.001至80μM或0.01至70μM。
本发明的另一个实施方式涉及式I的化合物、其溶剂化物、立体异构体或药学上可接受的盐,其用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病。
本发明的另一个实例涉及式I的化合物、其溶剂化物、立体异构体或药学上可接受的盐用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病的用途。
本发明的另一个实例涉及式I的化合物、其溶剂化物、立体异构体或药学上可接受的盐在制备用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病的药物的用途。
在下文中,将通过实施例更详细地描述本发明。这些实施例用于更详细地解释本发明,并且对于本领域技术人员显而易见的是,根据本发明的要点,本发明的范围不局限于这些实施例。
本发明的式I表示的嘧啶衍生化合物可以通过以下反应方案中说明的方法来制备,但不限于此。
式I表示的化合物的合成方法
根据本发明的式I表示的化合物可参照以下反应方案表示的方法进行制备:
方案(实施例1)
步骤1:6-氯-N-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-4-胺的合成
将嘧啶衍生化合物(1.0当量)溶解在异丙醇中,并且在室温下向其中添加苯胺衍生物(1.0当量)和甲烷磺酸(1.3当量),随后在80℃下搅拌过夜。反应完成后,通过减压蒸发去除溶剂,并且使用水和乙酸乙酯进行萃取。将有机层减压蒸发并进行柱色谱,从而得到目标化合物。
步骤2:N4-(4-氟-2-甲氧基-5硝基苯基)-N6-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-4,6-二胺的合成
将嘧啶衍生化合物(1.0当量)溶解在异丙醇中,并且在室温下向其中添加苯胺衍生物(1.0当量)和甲烷磺酸(1.3当量),随后在80℃下搅拌过夜。反应完成后,通过减压蒸发去除溶剂,并且使用水和乙酸乙酯进行萃取。将有机层减压蒸发并进行柱色谱,从而得到目标化合物。
步骤3:N4-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-N6-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-4,6-二胺的合成
将N4-(4-氟-2-甲氧基-5-硝基苯基)-N6-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-4,6-二胺(1.0当量)溶解在乙腈中,并且在室温下向其中添加碳酸钾(3.0当量)和胺链(1.2当量),随后回流并搅拌过夜。反应完成后,将温度降至室温并进行过滤。将滤液减压蒸发并进行柱色谱,从而得到目标化合物(二氯甲烷:甲醇=10:1)。
步骤4:N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基-N4-(6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)苯-1,2,4-三胺的合成
将N4-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-N6-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-4,6-二胺(1.0当量)溶解在1,4-二氧六环中,并且在室温下向其中添加锌(10.0当量)和氯化铵(10.0当量),随后搅拌过夜。反应完成后,将温度降至室温,并且用硅藻土进行过滤,然后使用水和乙酸乙酯对滤液进行萃取。将有机层收集、干燥,然后减压蒸发,从而得到化合物。将其用于下一个反应而无需进行分离。
步骤5:N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的合成
将N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基-N4-(6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)苯-1,2,4-三胺(1.0当量)溶解在四氢呋喃和水中,并且在0±0.5℃下向其中添加3-氯丙酰氯(1.2当量),随后在相同的温度下搅拌15分钟。反应完成后,在相同的温度下向其中添加氢氧化钠(4.0当量)。提高反应器温度并在65℃下搅拌过夜。反应完成后,通过减压蒸发去除溶剂,并且使用水和二氯甲烷进行萃取。将有机层减压蒸发并进行柱色谱,从而得到目标化合物(二氯甲烷:甲醇=10:1)。
实施例1.N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
产率:32.0%,白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),2.81(t,J=5.8Hz,2H),2.66(s,3H),2.26(q,J=5.9Hz,2H),2.16(s,6H).MS:ESI m/z542.1[M+H]+
实施例2.N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1中使用2-(1H-吡唑-1-基)苯胺,并且实验使用实施例1的方法。
产率:35.0%,白色固体,1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.97(s,1H),8.43(s,1H),8.30(s,1H),8.10(d,J=2.4Hz,1H),8.03(d,J=0.9Hz,1H),7.75(d,J=1.9Hz,1H),7.73(dd,J=8.1,1.4Hz,1H),7.50(dd,J=8.0,1.5Hz,1H),7.32(td,J=7.7,1.6Hz,1H),7.18(td,J=7.7,1.4Hz,1H),6.92(s,1H),6.47(t,J=2.2Hz,1H),6.33(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.2Hz,1H),5.93(s,1H),5.72-5.68(m,1H),3.72(s,3H),2.79(t,J=5.8Hz,2H),2.64(s,3H),2.24(t,J=5.8Hz,2H),2.15(s,6H).MS:ESI m/z528.2835[M+H]+
实施例3.N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-异丙氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
在步骤2中使用4-氟-2-异丙氧基-5-硝基苯胺,并且实验使用实施例1的方法。
产率:19.6%,白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),4.64(hept,J=6.8Hz,1H),3.76(s,3H),2.81(t,J=5.8Hz,2H),2.66(s,3H),2.26(q,J=5.9Hz,2H),2.16(s,6H),1.28(d,J=6.8Hz,6H).MS:ESI m/z 570.1[M+H]+
实施例4.N-(4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺的制备
使用实施例1的方法,并且在步骤3中使用1-甲基哌嗪。
产率:23.5%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),2.83-2.80(m,4H),2.42(m,4H),2.20(s,3H).MS:ESI m/z 540.0[M+H]+
实施例5.N-(4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-吗啉基苯基)丙烯酰胺的制备
使用实施例1的方法,并且在步骤3中使用吗啉。
产率:22.1%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),3.71-3.68(m,4H),2.81-2.79(m,4H).MS:ESI m/z 527.0[M+H]+
实施例6.(S)-N-(2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
使用实施例1的方法,并且在步骤3中使用(S)-N,N-二甲基吡咯烷-3-胺。
产率:18.4%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),3.37-3.30(m,1H),3.17-3.13(m,3H),2.64-2.57(m,1H),2.11(s,6H),2.05-1.99(m,1H),1.70-1.61(m,1H).MS:ESI m/z 534.1[M+H]+
实施例7.(R)-N-(2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
使用实施例1的方法,并且在步骤3中使用(R)-N,N-二甲基吡咯烷-3-胺。
产率:17.8%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),3.37-3.30(m,1H),3.17-3.13(m,3H),2.64-2.57(m,1H),2.11(s,6H),2.05-1.99(m,1H),1.70-1.61(m,1H).MS:ESI m/z 534.1[M+H]+
实施例8.(R)-N-(4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
使用实施例1的方法,并且在步骤3中使用(R)-N,1-二甲基吡咯烷-3-胺。
产率:22.2%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),3.58-3.51(m,1H),2.54-2.49(m,4H),2.45-2.42(m,1H),2.39-2.33(m,2H),1.90-1.81(m,1H),1.71-1.63(m,1H).MS:ESI m/z 534.1[M+H]+
实施例9.(S)-N-(4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
使用实施例1的方法,并且在步骤3中使用(S)-N,1-二甲基吡咯烷-3-胺。
产率:20.1%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),10.08(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.88(s,3H),3.76(s,3H),3.58-3.51(m,1H),2.54-2.49(m,4H),2.45-2.42(m,1H),2.39-2.33(m,2H),1.90-1.81(m,1H),1.71-1.63(m,1H).MS:ESI m/z 534.1[M+H]+
实施例10.N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-4-(2,2,2-三氟乙氧基)苯基)丙烯酰胺的制备
在步骤2中使用4-氟-5-硝基-2-(2,2,2-三氟乙氧基)苯胺,并且实验使用实施例1的方法。
产率:21.2%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),10.06(s,1H),8.47(s,1H),8.29(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),4.61-4.59(m,2H),3.76(s,3H),2.81(t,J=5.8Hz,2H),2.66(s,3H),2.26(q,J=5.9Hz,2H),2.17(s,6H).MS:ESI m/z 610.1[M+H]+
实施例11.N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-乙氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺的制备
在步骤2中使用2-乙氧基-4-氟-5-硝基苯胺,并且实验使用实施例1的方法。
产率:31.2%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),10.07(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),4.10(q,J=7.8Hz,2H),3.76(s,3H),2.81(t,J=5.8Hz,2H),2.66(s,3H),2.26(q,J=5.9Hz,2H),2.16(s,6H),1.40(t,J=7.9Hz,3H).MS:ESI m/z 556.1[M+H]+
实施例12.N-(4-环丙氧基-2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺的制备
在步骤2中使用2-环丙氧基-4-氟-5-硝基苯胺,并且实验使用实施例1的方法。
产率:29.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),10.06(s,1H),8.51(s,1H),8.31(s,1H),8.16(d,J=0.9Hz,1H),8.08(dd,J=8.3,1.2Hz,1H),7.78(d,J=2.3Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.20(ddd,J=8.5,7.2,1.6Hz,1H),6.99(td,J=7.5,1.2Hz,1H),6.95(s,1H),6.71(d,J=2.4Hz,1H),6.34(dd,J=16.9,10.0Hz,1H),6.18(dd,J=17.0,2.1Hz,1H),6.14(d,J=1.1Hz,1H),5.74-5.67(m,1H),3.76(s,3H),3.42-3.33(m,1H),2.81(t,J=5.8Hz,2H),2.66(s,3H),2.26(q,J=5.9Hz,2H),2.16(s,6H),0.60-0.57(m,2H),0.37-0.34(m,2H).MS:ESI m/z 568.1[M+H]+
实施例13.N-(5-((5-氰基-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1-1中使用2,4-二氯嘧啶-5-甲腈,并且实验使用实施例1的方法。
产率:19.5%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.37(s,1H),8.33(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),2.84(t,J=5.9Hz,2H),2.69(s,3H),2.28(t,J=5.7Hz,2H),2.17(s,6H).MS:ESI m/z 567.1[M+H]+
实施例14.N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1-1中使用2-(1H-吡唑-1-基)苯胺、2,4-二氯-5-甲基嘧啶,并且实验使用实施例1的方法。
产率:21.3%,灰白色固体,1H NMR(400MHz,DMSO-D6)δ10.05(s,1H),9.89(s,1H),8.34(d,J=14.0Hz,2H),8.29(s,1H),8.24(d,J=2.4Hz,1H),7.94(s,1H),7.88(d,J=1.8Hz,1H),7.49(dd,J=7.5,2.0Hz,1H),7.16-7.04(m,2H),6.96(s,1H),6.58-6.53(m,1H),6.35(dd,J=16.9,10.1Hz,1H),6.15(dd,J=16.9,2.1Hz,1H),5.74-5.66(m,1H),3.72(s,3H),2.83(t,J=5.9Hz,2H),2.68(s,3H),2.26(t,J=5.9Hz,2H),2.16(s,6H),2.09(s,3H).MS:ESI m/z 542.1[M+H]+
实施例15.N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)丙烯酰胺的制备
在步骤1-1中使用2,4-二氯-5-(三氟甲基)嘧啶,并且实验使用实施例1的方法。
产率:17.5%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.58(s,1H),8.76(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),2.84(t,J=5.9Hz,2H),2.69(s,3H),2.28(t,J=5.7Hz,2H),2.17(s,6H).MS:ESI m/z 610.0[M+H]+
方案(实施例16):
步骤1-1:2-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的合成
将苯胺衍生物(1.0当量)溶解在异丙醇中,并且在室温下向其中添加2,4-二氯嘧啶-5-甲酸异丙酯(1.1当量)和N,N-二异丙基乙胺(2.5当量),随后在80℃下搅拌过夜。反应完成后,进行减压蒸发,并且使用水和二氯甲烷进行萃取。将有机层用2N盐酸洗涤。将有机层减压蒸发并进行柱色谱,从而得到目标化合物。
实施例16.2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法。
产率:19.4%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.90(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(hept,J=6.1Hz,1H),3.88(s,3H),3.72(s,3H),2.92(m,2H),2.64(s,3H),2.28(m,6H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 628.2[M+H]+
实施例17.4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸异丙酯的制备
在步骤1-1中使用2-(1H-吡唑-1-基)苯胺,并且除了步骤1-1之外,所有实验都使用实施例1的方法。
产率:20.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.06(s,1H),8.91(s,1H),8.56(s,1H),8.26(s,1H),8.08(s,1H),8.00(d,J=2.4Hz,1H),7.73(dd,J=1.8,0.6Hz,1H),7.30(d,J=7.5Hz,1H),7.06(s,2H),6.97(s,1H),6.50-6.44(m,1H),6.37(dd,J=16.8,10.1Hz,1H),6.17(dd,J=16.9,2.1Hz,1H),5.71(dd,J=10.1,2.1Hz,1H),5.00(hept,J=6.3Hz,1H),3.71(s,3H),2.84(s,2H),2.68(s,3H),2.19(s,8H),1.24(d,J=6.2Hz,6H).MS:ESI m/z 614.1[M+H]+
实施例18.2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸甲酯的制备
在步骤1-1中使用2,4-二氯嘧啶-5-甲酸甲酯,并且所有实验都使用实施例1的方法。
产率:16.7%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.90(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),3.92(s,3H),3.88(s,3H),3.72(s,3H),2.92(m,2H),2.64(s,3H),2.28(m,8H).MS:ESI m/z 600.1[M+H]+
实施例19.4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸甲酯的制备
在步骤1-1中使用2-(1H-吡唑-1-基)苯胺和2,4-二氯嘧啶-5-甲酸甲酯,并且所有实验都使用实施例1的方法。
产率:17.4%,灰白色固体,NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.06(s,1H),8.91(s,1H),8.56(s,1H),8.26(s,1H),8.08(s,1H),8.00(d,J=2.4Hz,1H),7.73(dd,J=1.8,0.6Hz,1H),7.30(d,J=7.5Hz,1H),7.06(s,2H),6.97(s,1H),6.50-6.44(m,1H),6.37(dd,J=16.8,10.1Hz,1H),6.17(dd,J=16.9,2.1Hz,1H),5.71(dd,J=10.1,2.1Hz,1H),3.92(s,3H),3.71(s,3H),2.84(s,2H),2.68(s,3H),2.29(s,2H),2.19(s,6H).MS:ESI m/z586.1[M+H]+
实施例20.2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸乙酯的制备
在步骤1-1中使用2,4-二氯嘧啶-5-甲酸乙酯,并且所有实验都使用实施例1的方法。
产率:19.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.90(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),4.38(q,J=8.0Hz,2H),3.88(s,3H),3.72(s,3H),2.92(m,2H),2.64(s,3H),2.28(m,8H),1.34(t,J=8.0Hz,3H).MS:ESI m/z 614.1[M+H]+
实施例21.4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸乙酯的制备
在步骤1-1中使用2-(1H-吡唑-1-基)苯胺和2,4-二氯嘧啶-5-甲酸乙酯,并且所有实验都使用实施例1的方法。
产率:19.6%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.06(s,1H),8.91(s,1H),8.56(s,1H),8.26(s,1H),8.08(s,1H),8.00(d,J=2.4Hz,1H),7.73(dd,J=1.8,0.6Hz,1H),7.30(d,J=7.5Hz,1H),7.06(s,2H),6.97(s,1H),6.50-6.44(m,1H),6.37(dd,J=16.8,10.1Hz,1H),6.17(dd,J=16.9,2.1Hz,1H),5.71(dd,J=10.1,2.1Hz,1H),4.38(q,J=8.0Hz,2H),3.71(s,3H),2.84(s,2H),2.68(s,3H),2.29(s,2H),2.19(s,6H),1.34(t,J=8.0Hz,3H).MS:ESI m/z 600.1[M+H]+
实施例22.2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸环丙酯的制备
在步骤1-1中使用2,4-二氯嘧啶-5-甲酸环丙酯,并且所有实验都使用实施例1的方法。
产率:19.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.90(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),3.88(s,3H),3.72(s,3H),3.37(m,1H),2.92(m,2H),2.64(s,3H),2.28(m,6H),0.44-0.39(m,2H),0.27-0.24(m,2H).MS:ESI m/z 626.1[M+H]+
实施例23.2-((5-丙烯酰氨基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用1-甲基哌嗪。
产率:31.2%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.90(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(h,J=6.1Hz,1H),3.88(s,3H),3.72(s,3H),2.83-2.80(m,4H),2.42(m,4H),2.21(s,3H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 626.1[M+H]+
实施例24.2-((5-丙烯酰氨基-2-甲氧基-4-吗啉基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用吗啉。
产率:27.7%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.90(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(h,J=6.1Hz,1H),3.88(s,3H),3.72(s,3H),3.71-3.68(m,4H),2.81-2.79(m,4H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 613.1[M+H]+
实施例25.(S)-2-((5-丙烯酰氨基-4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(S)-N,N-二甲基吡咯烷-3-胺。
产率:22.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),9.92(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(h,J=6.1Hz,1H),3.86(s,3H),3.71(s,3H),3.37-3.30(m,1H),3.17-3.13(m,3H),2.64-2.57(m,1H),2.11(s,6H),2.05-1.99(m,1H),1.70-1.61(m,1H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 640.1[M+H]+
实施例26.(R)-2-((5-丙烯酰氨基-4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(R)-N,N-二甲基吡咯烷-3-胺。
产率:20.1%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),9.92(s,1H),8.76(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(h,J=6.1Hz,1H),3.86(s,3H),3.71(s,3H),3.37-3.30(m,1H),3.17-3.13(m,3H),2.64-2.57(m,1H),2.11(s,6H),2.05-1.99(m,1H),1.70-1.61(m,1H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 640.1[M+H]+
实施例27.(R)-2-((5-丙烯酰氨基-2-甲氧基-4-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(R)-N,1-二甲基吡咯烷-3-胺。
产率:21.1%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.91(s,1H),8.73(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(h,J=6.1Hz,1H),3.85(s,3H),3.70(s,3H),3.58-3.51(m,1H),2.54-2.49(m,4H),2.45-2.42(m,1H),2.39-2.33(m,2H),1.90-1.81(m,1H),1.71-1.63(m,1H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 640.1[M+H]+
实施例28.(S)-2-((5-丙烯酰氨基-2-甲氧基-4-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯的制备
除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(S)-N,1-二甲基吡咯烷-3-胺。
产率:18.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.91(s,1H),8.73(s,1H),8.60(s,1H),8.23(s,1H),8.16(s,1H),7.73(d,J=2.3Hz,1H),7.46(d,J=7.1Hz,1H),6.94(s,3H),6.48(d,J=2.3Hz,1H),6.18(d,J=16.7Hz,1H),5.71(dd,J=10.3,1.8Hz,1H),5.07(h,J=6.1Hz,1H),3.85(s,3H),3.70(s,3H),3.58-3.51(m,1H),2.54-2.49(m,4H),2.45-2.42(m,1H),2.39-2.33(m,2H),1.90-1.81(m,1H),1.71-1.63(m,1H),1.27(d,J=6.2Hz,6H).MS:ESI m/z 640.1[M+H]+
实施例29.N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,并且除了步骤1-1之外,所有实验都使用实施例1的方法。
产率:28.4%,淡黄色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),2.84(t,J=5.9Hz,2H),2.69(s,3H),2.28(t,J=5.7Hz,2H),2.17(s,6H).MS:ESI m/z 576.2586[M+H]+
实施例30.N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)-5-氯嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,并且除了步骤1-1之外,所有实验都使用实施例1的方法。
产率:37.6%,灰白色固体,1H NMR(400MHz,DMSO-D6)δ10.30(s,1H),10.07(s,1H),8.34(d,J=14.0Hz,2H),8.29(s,1H),8.24(d,J=2.4Hz,1H),8.06(s,1H),7.88(d,J=1.8Hz,1H),7.49(dd,J=7.5,2.0Hz,1H),7.16-7.04(m,2H),6.96(s,1H),6.58-6.53(m,1H),6.35(dd,J=16.9,10.1Hz,1H),6.15(dd,J=16.9,2.1Hz,1H),5.74-5.66(m,1H),3.72(s,3H),2.83(t,J=5.9Hz,2H),2.68(s,3H),2.26(t,J=5.9Hz,2H),2.16(s,6H).MS:ESIm/z 562.2453[M+H]+
实施例31.N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用1-甲基哌嗪。
产率:20.0%,淡黄色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),2.83-2.80(m,4H),2.42(m,4H),2.20(s,3H).MS:ESI m/z 574.1[M+H]+
实施例32.N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-吗啉基苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用吗啉。
产率:23.2%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),3.71-3.68(m,4H),2.81-2.79(m,4H).MS:ESI m/z 561.0[M+H]+
实施例33.(S)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(S)-N,N-二甲基吡咯烷-3-胺。
产率:19.0%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),3.37-3.30(m,1H),3.17-3.13(m,3H),2.64-2.57(m,1H),2.11(s,6H),2.05-1.99(m,1H),1.70-1.61(m,1H).MS:ESI m/z 588.0[M+H]+
实施例34.(R)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(R)-N,N-二甲基吡咯烷-3-胺。
产率:19.0%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),3.37-3.30(m,1H),3.17-3.13(m,3H),2.64-2.57(m,1H),2.11(s,6H),2.05-1.99(m,1H),1.70-1.61(m,1H).MS:ESI m/z 588.0[M+H]+
实施例35.(R)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(R)-N,1-二甲基吡咯烷-3-胺。
产率:20.3%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),3.58-3.51(m,1H),2.54-2.49(m,4H),2.45-2.42(m,1H),2.39-2.33(m,2H),1.90-1.81(m,1H),1.71-1.63(m,1H).MS:ESI m/z 588.0[M+H]+
实施例36.(S)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)丙烯酰胺的制备
在步骤1-1中使用2,4,5-三氯嘧啶,除了步骤1-1之外,所有实验都使用实施例1的方法,并且在步骤3中使用(S)-N,1-二甲基吡咯烷-3-胺。
产率:19.7%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.07(s,1H),8.57(d,J=8.1Hz,1H),8.39(s,1H),8.33(s,1H),8.10(s,1H),7.82(d,J=2.3Hz,1H),7.68(dd,J=7.6,1.9Hz,1H),7.06-6.92(m,3H),6.76(d,J=2.4Hz,1H),6.35(dd,J=16.9,10.1Hz,1H),6.13(dd,J=17.0,2.0Hz,1H),5.68(dd,J=10.1,2.1Hz,1H),3.91(s,3H),3.72(s,3H),3.58-3.51(m,1H),2.54-2.49(m,4H),2.45-2.42(m,1H),2.39-2.33(m,2H),1.90-1.81(m,1H),1.71-1.63(m,1H).MS:ESI m/z 588.0[M+H]+
方案(实施例37):
步骤1:N-(2-(1H-吡唑-1-基)苯基)-6-氯嘧啶-4-胺的合成
将嘧啶衍生化合物(1.0当量)溶解在异丙醇中,并且在室温下向其中添加苯胺衍生物(1.0当量)和甲烷磺酸(1.3当量),随后在80℃下搅拌过夜。反应完成后,通过减压蒸发去除溶剂,并且使用水和乙酸乙酯进行萃取。将有机层减压蒸发并进行柱色谱,从而得到目标化合物。
步骤2:N4-(2-(1H-吡唑-1-基)苯基)-N6-(4-氟-2-甲氧基-5硝基苯基)嘧啶-4,6-二胺的合成
将嘧啶衍生化合物(1.0当量)溶解在异丙醇中,并且在室温下向其中添加苯胺衍生物(1.0当量)和甲烷磺酸(1.3当量),随后在80℃下搅拌过夜。反应完成后,通过减压蒸发去除溶剂,并且使用水和乙酸乙酯进行萃取。将有机层减压蒸发并进行柱色谱,从而得到目标化合物。
步骤3:N4-(2-(1H-吡唑-1-基)苯基)-N6-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)嘧啶-4,6-二胺的合成
将N4-(2-(1H-吡唑-1-基)苯基)-N6-(4-氟-2-甲氧基-5-硝基苯基)嘧啶-4,6-二胺(1.0当量)溶解在乙腈中,并且在室温下向其中添加碳酸钾(3.0当量)和胺链(1.2当量),随后回流并搅拌过夜。反应完成后,将温度降至室温并进行过滤。将滤液减压蒸发并进行柱色谱,从而得到目标化合物(二氯甲烷:甲醇=10:1)。
步骤4:N4-(6-((2-(1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基苯-1,2,4-三胺的合成
将N4-(2-(1H-吡唑-1-基)苯基)-N6-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)嘧啶-4,6-二胺(1.0当量)溶解在1,4-二氧六环中,并且在室温下向其中添加锌(10.0当量)和氯化铵(10.0当量),随后在室温下搅拌过夜。反应完成后,将温度降至室温,并且用硅藻土进行过滤,然后使用水和乙酸乙酯对滤液进行萃取。将有机层收集、干燥,然后减压蒸发,从而得到化合物。将其用于下一个反应而无需进行分离。
步骤5:N-5-((6-((2-(1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的合成
将N4-(6-((2-(1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基苯-1,2,4-三胺(1.0当量)溶解在乙腈中,并且在0±0.5℃下向其中添加3-氯丙酰氯(1.2当量),随后在相同的温度下搅拌15分钟。反应完成后,在相同的温度下向其中添加三乙胺(4.0当量)。提高反应器温度并在65℃下搅拌过夜。反应完成后,通过减压蒸发去除溶剂,并且使用水和二氯甲烷进行萃取。将有机层减压蒸发并进行柱色谱,从而得到目标化合物(二氯甲烷:甲醇=10:1)。
实施例37.N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二乙基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
产率:35%,白色固体,1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.96(s,1H),8.36(s,1H),8.27(s,1H),8.10(dd,J=2.5,0.6Hz,1H),8.03(d,J=0.9Hz,1H),7.75(dd,J=1.8,0.6Hz,1H),7.73(dd,J=8.2,1.4Hz,1H),7.50(dd,J=8.0,1.5Hz,1H),7.32(td,J=7.7,1.6Hz,1H),7.18(td,J=7.6,1.4Hz,1H),6.88(s,1H),6.48(dd,J=2.5,1.8Hz,1H),6.41(dd,J=16.9,10.1Hz,1H),6.19(dd,J=17.0,2.1Hz,1H),5.92(d,J=1.0Hz,1H),5.70(dd,J=10.0,2.0Hz,1H),3.73(s,3H),3.33-3.25(m,2H),2.78(t,J=6.1Hz,2H),2.64(s,3H),2.49(m,2H),2.44-2.38(m,2H),0.90(t,J=7.1Hz,6H).MS:ESI m/z556.3151[M+H]+
实施例38.N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-4-甲氧基-2-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)苯基)丙烯酰胺的制备
在步骤3中使用六氢-1H-呋喃并[3,4-c]吡咯进行合成。
产率:31.0%,白色固体,1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.95(s,1H),8.25(s,1H),8.10(d,J=2.5Hz,1H),8.02(s,1H),7.82-7.70(m,3H),7.51(dd,J=7.9,1.5Hz,1H),7.34(t,J=7.8Hz,1H),7.19(t,J=7.6Hz,1H),6.63(s,1H),6.54-6.40(m,2H),6.22-6.11(m,1H),5.90(s,1H),5.73-5.62(m,1H),3.79(t,J=7.3Hz,2H),3.74(s,3H),3.56-3.41(m,2H),3.14-3.02(m,2H),2.82(m,4H).MS:ESI m/z 539.2550[M+H]+
实施例39.N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-甲氧基苯基)丙烯酰胺的制备
在步骤3中使用3-氧杂-8-氮杂双环[3.2.1]辛烷进行合成。
产率:30.0%,白色固体,1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.95(s,1H),8.23(s,1H),8.10(d,J=2.4Hz,1H),8.02(s,1H),7.82-7.68(m,3H),7.51(dd,J=8.0,1.5Hz,1H),7.33(t,J=7.8Hz,1H),7.19(t,J=7.6Hz,1H),6.55(dd,J=17.0,10.2Hz,1H),6.48(q,J=2.0,1.5Hz,2H),6.17(dd,J=17.1,1.9Hz,1H),5.88(s,1H),5.67(dd,J=10.5,1.7Hz,1H),3.81(d,J=10.1Hz,2H),3.73(s,3H),3.58(s,2H),3.50(d,J=10.0Hz,2H),1.84(s,4H).MS:ESI m/z 539.2533[M+H]+
[表1]
实施例1至39的化合物
<测试例>癌细胞生长抑制作用的测定
由于没有市售的具有EGFR插入突变的肺癌细胞系,因此尝试了在野生型EGFR表达载体中使用定点诱变在每个位点插入3至4个氨基酸的方法。在本发明中,首先,使用在频率最高的D770_N771位点添加了3个氨基酸NPG的载体,并且Ba/F3细胞系用于表达这些基因。
Ba/F3细胞系是仅在添加IL-3时才表现出细胞生长的鼠类pro B细胞系。当表达致癌突变体EGFR时,在没有IL-3的情况下发生细胞生长和凋亡依赖于突变体EGFR。因此,对突变体EGFR表现出有效抑制的物质会抑制细胞生长并诱导凋亡,因此通过MTT测定分析细胞的抗癌作用。
将1×104个先前构建稳定的细胞放入96孔板并温育过夜,然后实施例的化合物是剂量依赖性处理的。72小时之后,添加MTT试剂,并且3小时后添加停止缓冲液(10% SDS)。温育24小时后,通过在595nm进行读取来分析结果。按照各个化合物抑制细胞生长达到50%的浓度计算IC50值,并且结果以A、B和C的形式在以下表1中示出(其中,A表示IC50小于25nM,B表示IC50小于50nM,并且C表示IC50为50至500nM)。使用莫博替尼作为对照药物。
[表2]
癌细胞生长抑制作用(IC50)的测定
如表2所示,通过本发明的实施例制备的化合物针对表达表皮生长因子受体外显子20插入突变的肺癌细胞系表现出优异的活性。实施例的化合物表现出与对照药物等同或优于对照药物(莫博替尼)的活性。因此,本发明提出了能够治疗与表达表皮生长因子受体外显子20插入突变基因或蛋白相关的疾病或表现出表皮生长因子受体外显子20插入突变的癌症的新型嘧啶衍生物。
Claims (17)
1.由以下式I表示的化合物、其溶剂化物、立体异构体或药学上可接受的盐:
<式I>
其中,
A、B和E各自独立地为N或CH,
D为N或C,
X为CH、N或O,
Y为CH、N或O,
L为单键或NR5,
R5为H或C1至C4烷基,
Z1和Z2各自独立地为C1至C4烷基,或者各自独立地包含碳并且相互连接,从而与X和Y形成5元至8元环,
Z3为(CH2)n,或者包含碳并且与Z1、Z2、X和Y形成5元至8元环,并且
n为1至3的整数,
R1为H、吡唑或被C1至C4烷基取代的吡唑,
R2为H、卤素、C1至C4烷基、C1至C4烷基酯、CN或被卤素取代的C1至C4烷基(然而,如果D为N,则R2不存在),
R3为H、C1至C5直链或支链烷基、被卤素取代的C1至C5烷基,或C3至C5环烷基,并且
R4不存在,或为H、C1至C4烷基、C1至C4单烷基或C1至C4二烷基胺。
2.如权利要求1所述的化合物、其溶剂化物、立体异构体和药学上可接受的盐,其中,所述Z1和Z2各自独立地包含碳并且相互连接,从而与X和Y形成5元至8元的单环、稠合双环或桥连双环。
3.如权利要求1所述的化合物、其溶剂化物、立体异构体和药学上可接受的盐,其中,以上式I中的A和D为N。
4.如权利要求1所述的化合物、其溶剂化物、立体异构体和药学上可接受的盐,其中,以上式I中的A和E为N。
5.如权利要求1所述的化合物、其溶剂化物、立体异构体和药学上可接受的盐,其中,在以上式I中,L为单键,并且X为N或O。
6.如权利要求1所述的化合物、其溶剂化物、立体异构体和药学上可接受的盐,其中,在以上式I中,L为NR5,并且X为CH,
其中,所述Z1和Z2各自独立地包含碳并且相互连接,从而与Z3、X和Y形成5元至8元的单环、稠合双环或桥连双环。
7.如权利要求1所述的化合物、其溶剂化物、立体异构体和药学上可接受的盐,其选自由以下化合物组成的组:
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-异丙氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺;
N-(4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-2-吗啉基苯基)丙烯酰胺;
(S)-N-(2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
(R)-N-(2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
(R)-N-(4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
(S)-N-(4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)-4-(2,2,2-三氟乙氧基)苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-乙氧基-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺;
N-(4-环丙氧基-2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((6-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺;
N-(5-((5-氰基-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)丙烯酰胺;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸异丙酯;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸甲酯;
4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸甲酯;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸乙酯;
4-((2-(1H-吡唑-1-基)苯基)氨基)-2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-5-甲酸乙酯;
2-((5-丙烯酰氨基-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸环丙酯;
2-((5-丙烯酰氨基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
2-((5-丙烯酰氨基-2-甲氧基-4-吗啉基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(S)-2-((5-丙烯酰氨基-4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(R)-2-((5-丙烯酰氨基-4-(3-(二甲氨基)吡咯烷-1-基)-2-甲氧基苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(R)-2-((5-丙烯酰氨基-2-甲氧基-4-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
(S)-2-((5-丙烯酰氨基-2-甲氧基-4-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)氨基)-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-5-甲酸异丙酯;
N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)-5-氯嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺;
N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-吗啉基苯基)丙烯酰胺;
(S)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺;
(R)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-(3-(二甲氨基)吡咯烷-1-基)-4-甲氧基苯基)丙烯酰胺;
(R)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)丙烯酰胺;
(S)-N-(5-((5-氯-4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(甲基(1-甲基吡咯烷-3-基)氨基)苯基)丙烯酰胺;
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-((2-(二乙基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺;
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-4-甲氧基-2-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)苯基)丙烯酰胺;以及
N-(5-((6-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-甲氧基苯基)丙烯酰胺。
8.一种用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病的药物组合物,所述药物组合物包含权利要求1至7中任一项所述的化合物、其溶剂化物、立体异构体或药学上可接受的盐。
9.如权利要求8所述的药物组合物,其中,所述药物组合物进一步包含药学上可接受的载体。
10.如权利要求8所述的药物组合物,其中,所述突变体EGFR为EGFR外显子20插入。
11.如权利要求8所述的药物组合物,其中,所述过表达突变体EGFR的疾病为癌症。
12.如权利要求11所述的药物组合物,其中,所述癌症为选自由肝癌、肝细胞癌、胃肠道癌、胃癌、与神经纤维瘤病相关的脑膜瘤、胰腺癌、白血病、骨髓增殖性疾病、骨髓增生异常疾病、皮肤纤维肉瘤、乳腺癌、肺癌、甲状腺癌、结直肠癌、前列腺癌、卵巢癌、脑肿瘤、头颈癌和成胶质细胞瘤组成的组中的至少一种。
13.如权利要求11所述的药物组合物,其中,所述癌症为非小细胞肺癌。
14.一种用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病的方法,其包括向受试者施用权利要求1至7中任一项所述的化合物、其溶剂化物、立体异构体或药学上可接受的盐的步骤。
15.如权利要求1至7中任一项所述的化合物、其溶剂化物、立体异构体或药学上可接受的盐,用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病。
16.权利要求1至7中任一项所述的化合物、其溶剂化物、立体异构体或药学上可接受的盐用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病的用途。
17.权利要求1至7中任一项所述的化合物、其溶剂化物、立体异构体或药学上可接受的盐用于预防或治疗过表达酪氨酸激酶结构域突变体EGFR的疾病的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0031948 | 2021-03-11 | ||
KR20210031948 | 2021-03-11 | ||
PCT/KR2022/003457 WO2022191664A1 (ko) | 2021-03-11 | 2022-03-11 | 암세포 성장 억제 효과를 나타내는 신규한 피리미딘 유도체 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117177968A true CN117177968A (zh) | 2023-12-05 |
Family
ID=83226938
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280029605.6A Withdrawn CN117177968A (zh) | 2021-03-11 | 2022-03-11 | 对癌细胞生长表现出抑制作用的新型嘧啶衍生物 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20240166663A1 (zh) |
EP (1) | EP4306518A1 (zh) |
JP (1) | JP2024509458A (zh) |
KR (1) | KR20220128590A (zh) |
CN (1) | CN117177968A (zh) |
AU (1) | AU2022232876A1 (zh) |
BR (1) | BR112023018281A2 (zh) |
CA (1) | CA3211588A1 (zh) |
WO (1) | WO2022191664A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022221227A1 (en) | 2021-04-13 | 2022-10-20 | Nuvalent, Inc. | Amino-substituted heterocycles for treating cancers with egfr mutations |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010129053A2 (en) * | 2009-05-05 | 2010-11-11 | Dana Farber Cancer Institute | Egfr inhibitors and methods of treating disorders |
MX2015009952A (es) * | 2013-02-08 | 2015-10-05 | Celgene Avilomics Res Inc | Inhibidores de cinasas reguladas por señales extracelulares (erk) y sus usos. |
CN106928150B (zh) * | 2015-12-31 | 2020-07-31 | 恩瑞生物医药科技(上海)有限公司 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
CN107098887B (zh) * | 2016-02-22 | 2019-08-09 | 复旦大学 | 嘧啶类化合物 |
CN106083736A (zh) * | 2016-06-21 | 2016-11-09 | 郑州泰基鸿诺医药股份有限公司 | 一种嘧啶类化合物、egfr抑制剂及其应用 |
-
2022
- 2022-03-11 CA CA3211588A patent/CA3211588A1/en active Pending
- 2022-03-11 AU AU2022232876A patent/AU2022232876A1/en active Pending
- 2022-03-11 US US18/281,058 patent/US20240166663A1/en active Pending
- 2022-03-11 KR KR1020220030929A patent/KR20220128590A/ko unknown
- 2022-03-11 JP JP2023555379A patent/JP2024509458A/ja not_active Withdrawn
- 2022-03-11 WO PCT/KR2022/003457 patent/WO2022191664A1/ko active Application Filing
- 2022-03-11 CN CN202280029605.6A patent/CN117177968A/zh not_active Withdrawn
- 2022-03-11 BR BR112023018281A patent/BR112023018281A2/pt unknown
- 2022-03-11 EP EP22767560.0A patent/EP4306518A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
AU2022232876A1 (en) | 2023-09-21 |
KR20220128590A (ko) | 2022-09-21 |
WO2022191664A1 (ko) | 2022-09-15 |
BR112023018281A2 (pt) | 2023-10-31 |
US20240166663A1 (en) | 2024-05-23 |
JP2024509458A (ja) | 2024-03-01 |
EP4306518A1 (en) | 2024-01-17 |
CA3211588A1 (en) | 2022-09-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7181558B2 (ja) | Egfrモジュレーターとしての置換2-アミノピリミジン誘導体 | |
US10059688B2 (en) | Protein tyrosine kinase modulators and methods of use | |
JP6524221B2 (ja) | Egfr変異型キナーゼ活性をモジュレートするための化合物および組成物 | |
CN107556295B (zh) | 喹唑啉衍生物及其制备方法 | |
US9890168B2 (en) | 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof | |
AU2017335242A1 (en) | Pyridine compound | |
KR102383200B1 (ko) | 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 | |
US10053449B2 (en) | Quinazoline derivatives, compositions thereof, and use as pharmaceuticals | |
WO2019149114A1 (zh) | 一种化合物或其药用盐或组合物的制备及应用 | |
CN109575045B (zh) | 噻吩并嘧啶类化合物、其制备方法、药用组合物及其应用 | |
CN117177968A (zh) | 对癌细胞生长表现出抑制作用的新型嘧啶衍生物 | |
CN114630819B (zh) | 用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法以及包含其作为活性成分的药物组合物 | |
CN112236422B (zh) | 喹唑啉类化合物作为egfr三突变抑制剂及其应用 | |
AU2021326209B2 (en) | EFGR inhibitor, preparation method therefor, and application thereof | |
JP2024527599A (ja) | 新規のピリミジン-2,4-ジアミン誘導体、その調製方法、ならびにそれを癌の予防または処置のための有効成分として含有する医薬組成物 | |
KR102685187B1 (ko) | Alk 및/또는 egfr 돌연변이 키나제 억제 효과를 나타내는 화합물 및 이의 의약 용도 | |
KR102568168B1 (ko) | 신규한 피리미딘-2,4-디아민 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물 | |
KR102383561B1 (ko) | 테트라히드로이소퀴놀린기로 치환된 피리미딘 유도체 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용 가능한 염, 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 조성물 | |
OA18657A (en) | Substituted 2-anilinopyrimidine derivatives as EGFR modulators. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WW01 | Invention patent application withdrawn after publication | ||
WW01 | Invention patent application withdrawn after publication |
Application publication date: 20231205 |