WO2018208132A1 - Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif - Google Patents
Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif Download PDFInfo
- Publication number
- WO2018208132A1 WO2018208132A1 PCT/KR2018/005478 KR2018005478W WO2018208132A1 WO 2018208132 A1 WO2018208132 A1 WO 2018208132A1 KR 2018005478 W KR2018005478 W KR 2018005478W WO 2018208132 A1 WO2018208132 A1 WO 2018208132A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- pyrimidine
- pyrazolo
- dimethylphenyl
- tetrahydroisoquinoline
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 239
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 68
- 201000011510 cancer Diseases 0.000 title claims abstract description 61
- 208000023275 Autoimmune disease Diseases 0.000 title claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 37
- 239000004480 active ingredient Substances 0.000 title claims abstract description 34
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 title abstract description 12
- 208000014644 Brain disease Diseases 0.000 title abstract description 4
- 238000011282 treatment Methods 0.000 claims abstract description 48
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 claims abstract description 40
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 claims abstract description 40
- 230000002265 prevention Effects 0.000 claims abstract description 35
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims description 411
- 239000000203 mixture Substances 0.000 claims description 137
- 239000007787 solid Substances 0.000 claims description 105
- 150000003839 salts Chemical class 0.000 claims description 77
- 238000006243 chemical reaction Methods 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- -1 -OH Chemical group 0.000 claims description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 230000036541 health Effects 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 19
- VXUDSMGBRZKEGZ-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C VXUDSMGBRZKEGZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- QVALNZJHSOYBQW-UHFFFAOYSA-N 3-N-(2,6-dichlorophenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound ClC1=C(C(=CC=C1)Cl)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C QVALNZJHSOYBQW-UHFFFAOYSA-N 0.000 claims description 12
- 235000013376 functional food Nutrition 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 230000006872 improvement Effects 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- DCIMEFIVIWONCF-UHFFFAOYSA-N 3-N-(2,6-dichlorophenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound ClC1=C(C(=CC=C1)Cl)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCNCC2=CC=1)C DCIMEFIVIWONCF-UHFFFAOYSA-N 0.000 claims description 6
- HKGVNSBFDYWVTK-UHFFFAOYSA-N 6-N-(1,1-dimethyl-3,4-dihydro-2H-isoquinolin-7-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1(NCCC2=CC=C(C=C12)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C)C HKGVNSBFDYWVTK-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- NMXHBWRULVLHFQ-UHFFFAOYSA-N 1-[6-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCN(CC2=CC=1OC)C(C(F)(F)F)=O)C NMXHBWRULVLHFQ-UHFFFAOYSA-N 0.000 claims description 5
- DXRLOIGEDOCAAI-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]prop-2-en-1-one Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C=C)=O)C DXRLOIGEDOCAAI-UHFFFAOYSA-N 0.000 claims description 5
- JNWCBZVEQWGJPQ-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C)C JNWCBZVEQWGJPQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001924 cycloalkanes Chemical class 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 201000005787 hematologic cancer Diseases 0.000 claims description 5
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 5
- MVADRBAVDXRHGR-UHFFFAOYSA-N tert-butyl 5-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,3-dihydroisoindole-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC2=CC=C(C=C2C1)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C MVADRBAVDXRHGR-UHFFFAOYSA-N 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- GIAMOPWGDZUOFJ-UHFFFAOYSA-N 1-[4-methyl-3-[[1-methyl-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound CC1=C(C=C(C=C1)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C GIAMOPWGDZUOFJ-UHFFFAOYSA-N 0.000 claims description 4
- VKQVLORENPCCLM-UHFFFAOYSA-N 1-[6-[[3-(2,6-dichloroanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound ClC1=C(C(=CC=C1)Cl)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCN(CC2=CC=1)C(C)=O)C VKQVLORENPCCLM-UHFFFAOYSA-N 0.000 claims description 4
- QJYBYHQOCLMSEC-UHFFFAOYSA-N 1-[6-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCN(CC2=CC=1OC)C(C)=O)C QJYBYHQOCLMSEC-UHFFFAOYSA-N 0.000 claims description 4
- RJTAWOHFJLPVOE-UHFFFAOYSA-N 1-[7-[[3-(2,6-dichloroanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound ClC1=C(C(=CC=C1)Cl)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C)=O)C RJTAWOHFJLPVOE-UHFFFAOYSA-N 0.000 claims description 4
- ZPUUFJAPWKGWHM-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2-hydroxyethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(CO)=O)C ZPUUFJAPWKGWHM-UHFFFAOYSA-N 0.000 claims description 4
- LIQDBRIFYIVYNC-UHFFFAOYSA-N 2-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethanol Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)CCO)C LIQDBRIFYIVYNC-UHFFFAOYSA-N 0.000 claims description 4
- IZTDIATUHNDTOK-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2H-pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NNC2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1 IZTDIATUHNDTOK-UHFFFAOYSA-N 0.000 claims description 4
- WLOOVECCLUTMQW-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-6-N-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCNCC2=CC=1OC)C WLOOVECCLUTMQW-UHFFFAOYSA-N 0.000 claims description 4
- HKEWAZIWKOPHIN-UHFFFAOYSA-N 3-N-[4-(2-methoxyethoxy)-2,6-dimethylphenyl]-1-methyl-6-N-(1-propan-2-yl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound C(C)(C)C1NCCC2=CC=C(C=C12)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OCCOC)C)C HKEWAZIWKOPHIN-UHFFFAOYSA-N 0.000 claims description 4
- ZFOFWOGXZQNDBB-UHFFFAOYSA-N 4-[3-(2,6-dimethylanilino)-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexan-1-ol Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C1CCC(CC1)O ZFOFWOGXZQNDBB-UHFFFAOYSA-N 0.000 claims description 4
- PEEJERRIKCEBQO-UHFFFAOYSA-N 6-N-(1,1-dimethyl-3,4-dihydro-2H-isoquinolin-7-yl)-3-N-[4-(2-methoxyethoxy)-2,6-dimethylphenyl]-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1(NCCC2=CC=C(C=C12)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OCCOC)C)C)C PEEJERRIKCEBQO-UHFFFAOYSA-N 0.000 claims description 4
- HTVAFBVYKVARRS-UHFFFAOYSA-N 6-N-(3,4-dihydro-1H-isochromen-7-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCOCC2=C1)C HTVAFBVYKVARRS-UHFFFAOYSA-N 0.000 claims description 4
- 208000032467 Aplastic anaemia Diseases 0.000 claims description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 4
- 206010039710 Scleroderma Diseases 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 210000004392 genitalia Anatomy 0.000 claims description 4
- KXQXVSQIUAMPIN-UHFFFAOYSA-N 1-[5-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,3-dihydroisoindol-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CN(CC2=CC=1)C(C)=O)C KXQXVSQIUAMPIN-UHFFFAOYSA-N 0.000 claims description 3
- XUIRRIUETBVSCC-UHFFFAOYSA-N 1-[6-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCN(CC2=CC=1)C(C(F)(F)F)=O)C XUIRRIUETBVSCC-UHFFFAOYSA-N 0.000 claims description 3
- HVZXAJDBZBRMLW-UHFFFAOYSA-N 1-[6-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCN(CC2=CC=1)C(C)=O)C HVZXAJDBZBRMLW-UHFFFAOYSA-N 0.000 claims description 3
- MBTQVGVIQRMCBJ-UHFFFAOYSA-N 1-[7-[(3-anilino-1-methylpyrazolo[3,4-d]pyrimidin-6-yl)amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound FC(C(=O)N1CC2=CC(=CC=C2CC1)NC1=NC=C2C(=N1)N(N=C2NC1=CC=CC=C1)C)(F)F MBTQVGVIQRMCBJ-UHFFFAOYSA-N 0.000 claims description 3
- CLNAAWOVFHAMMY-UHFFFAOYSA-N 1-[7-[[3-(2,6-dichloroanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound ClC1=C(C(=CC=C1)Cl)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C(F)(F)F)=O)C CLNAAWOVFHAMMY-UHFFFAOYSA-N 0.000 claims description 3
- PNRISZFDTHKTDQ-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(C(C2=C1)(C)C)C(C)=O)C PNRISZFDTHKTDQ-UHFFFAOYSA-N 0.000 claims description 3
- NXAHGPRAVXMOQZ-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,3,3-trimethyl-1,4-dihydroisoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CC(N(C(C2=C1)C)C(C)=O)(C)C)C NXAHGPRAVXMOQZ-UHFFFAOYSA-N 0.000 claims description 3
- RRBUVIGNFMHGDW-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(C(C2=C1)C)C(C)=O)C RRBUVIGNFMHGDW-UHFFFAOYSA-N 0.000 claims description 3
- FDVJFNHHHQUBIS-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1-propan-2-yl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(C(C2=C1)C(C)C)C(C)=O)C FDVJFNHHHQUBIS-UHFFFAOYSA-N 0.000 claims description 3
- DMRMPTOYXVVJHH-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,3-dimethyl-1,4-dihydroisoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CC(N(CC2=C1)C(C)=O)(C)C)C DMRMPTOYXVVJHH-UHFFFAOYSA-N 0.000 claims description 3
- XKQJEDHVHSYKJJ-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C)=O)C XKQJEDHVHSYKJJ-UHFFFAOYSA-N 0.000 claims description 3
- YIMDTHNJTRUHAK-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-4,4-dimethyl-1,3-dihydroisoquinolin-2-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2C(CN(CC2=C1)C(C)=O)(C)C)C YIMDTHNJTRUHAK-UHFFFAOYSA-N 0.000 claims description 3
- SCWYPRWJHALKTA-UHFFFAOYSA-N 1-cyclohexyl-3-N-(2,6-dimethylphenyl)-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound C1(CCCCC1)N1N=C(C=2C1=NC(=NC=2)NC1=CC=C2CCNCC2=C1)NC1=C(C=CC=C1C)C SCWYPRWJHALKTA-UHFFFAOYSA-N 0.000 claims description 3
- IXGPWZLWQBOMFU-UHFFFAOYSA-N 1-cyclopentyl-3-N-(2,6-dimethylphenyl)-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound C1(CCCC1)N1N=C(C=2C1=NC(=NC=2)NC1=CC=C2CCNCC2=C1)NC1=C(C=CC=C1C)C IXGPWZLWQBOMFU-UHFFFAOYSA-N 0.000 claims description 3
- KXSPMFYBIOAMBO-UHFFFAOYSA-N 1-methyl-3-N-(2-methylphenyl)-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CN1N=C(C=2C1=NC(=NC=2)NC1=CC=C2CCNCC2=C1)NC1=C(C=CC=C1)C KXSPMFYBIOAMBO-UHFFFAOYSA-N 0.000 claims description 3
- YBLONGQUHUAXDG-UHFFFAOYSA-N 1-methyl-3-N-phenyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CN1N=C(C=2C1=NC(=NC=2)NC1=CC=C2CCNCC2=C1)NC1=CC=CC=C1 YBLONGQUHUAXDG-UHFFFAOYSA-N 0.000 claims description 3
- XGXCCYYVJPMQNT-UHFFFAOYSA-N 2-(dimethylamino)-1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound CN(CC(=O)N1CC2=CC(=CC=C2CC1)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C)C XGXCCYYVJPMQNT-UHFFFAOYSA-N 0.000 claims description 3
- HKHNZWMSAHBGEP-UHFFFAOYSA-N 3,5-dimethyl-4-[[1-methyl-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-yl]amino]-N-pyridin-2-ylbenzamide Chemical compound CC=1C=C(C(=O)NC2=NC=CC=C2)C=C(C=1NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C)C HKHNZWMSAHBGEP-UHFFFAOYSA-N 0.000 claims description 3
- LXCNSVYAXNNIHD-UHFFFAOYSA-N 3-N-(2,4-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C=CC(=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C LXCNSVYAXNNIHD-UHFFFAOYSA-N 0.000 claims description 3
- OJBIOWUTKWEAHQ-UHFFFAOYSA-N 3-N-(2,5-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C=C(C=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C OJBIOWUTKWEAHQ-UHFFFAOYSA-N 0.000 claims description 3
- UDLLVWGJVOLGDE-UHFFFAOYSA-N 3-N-(2,6-diethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound C(C)C1=C(C(=CC=C1)CC)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C UDLLVWGJVOLGDE-UHFFFAOYSA-N 0.000 claims description 3
- AZFMLDPTRAJNLH-UHFFFAOYSA-N 3-N-(2,6-difluorophenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound FC1=C(C(=CC=C1)F)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C AZFMLDPTRAJNLH-UHFFFAOYSA-N 0.000 claims description 3
- VOFGKLIXKMFTNN-UHFFFAOYSA-N 3-N-(2,6-dimethoxyphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound COC1=C(C(=CC=C1)OC)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C VOFGKLIXKMFTNN-UHFFFAOYSA-N 0.000 claims description 3
- OHUQRNAQCGGIFF-UHFFFAOYSA-N 3-N-(2,6-dimethyl-4-phenoxyphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC(=C1)OC1=CC=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C OHUQRNAQCGGIFF-UHFFFAOYSA-N 0.000 claims description 3
- BBAUTFZWTSOLNB-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1,1,2-trimethyl-3,4-dihydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(C(C2=C1)(C)C)C)C BBAUTFZWTSOLNB-UHFFFAOYSA-N 0.000 claims description 3
- SEUJYTOQXKRZNO-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1,2,3,3-tetramethyl-1,4-dihydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CC(N(C(C2=C1)C)C)(C)C)C SEUJYTOQXKRZNO-UHFFFAOYSA-N 0.000 claims description 3
- NDCZVCONOHVRJH-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCNCC2=CC=1)C NDCZVCONOHVRJH-UHFFFAOYSA-N 0.000 claims description 3
- XESVQXXXRPRPKW-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNC(C2=C1)C)C XESVQXXXRPRPKW-UHFFFAOYSA-N 0.000 claims description 3
- RFYAOUHGAHUGGZ-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1-propan-2-yl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNC(C2=C1)C(C)C)C RFYAOUHGAHUGGZ-UHFFFAOYSA-N 0.000 claims description 3
- NJLVIILKVLPAIT-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(2,3,3-trimethyl-1,4-dihydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CC(N(CC2=C1)C)(C)C)C NJLVIILKVLPAIT-UHFFFAOYSA-N 0.000 claims description 3
- UXCJSNVUZHCWMV-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(2,4,4-trimethyl-1,3-dihydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2C(CN(CC2=C1)C)(C)C)C UXCJSNVUZHCWMV-UHFFFAOYSA-N 0.000 claims description 3
- MNMTXHRDUIKTKX-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(2-methyl-1,3-dihydroisoindol-5-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CN(CC2=CC=1)C)C MNMTXHRDUIKTKX-UHFFFAOYSA-N 0.000 claims description 3
- FUISOKIMDGXMHR-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(2-methyl-1-propan-2-yl-3,4-dihydro-1H-isoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(C(C2=C1)C(C)C)C)C FUISOKIMDGXMHR-UHFFFAOYSA-N 0.000 claims description 3
- KZMRWEFLSUIQSY-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(2-propan-2-yl-3,4-dihydro-1H-isoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C)C)C KZMRWEFLSUIQSY-UHFFFAOYSA-N 0.000 claims description 3
- IHFGFVZWLCKLDI-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=2CCCCC=2C=C1)C IHFGFVZWLCKLDI-UHFFFAOYSA-N 0.000 claims description 3
- GXLUVRARXKQZRI-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-propan-2-yl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C(C)C GXLUVRARXKQZRI-UHFFFAOYSA-N 0.000 claims description 3
- CJOTZPZVJHIHEO-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-6-N-(2-ethyl-3,4-dihydro-1H-isoquinolin-7-yl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)CC)C CJOTZPZVJHIHEO-UHFFFAOYSA-N 0.000 claims description 3
- QXPVYHCCSNDDKD-UHFFFAOYSA-N 3-N-(2-chloro-3,5-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound ClC1=C(C=C(C=C1C)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C QXPVYHCCSNDDKD-UHFFFAOYSA-N 0.000 claims description 3
- DUPRBTZWZRETAB-UHFFFAOYSA-N 3-N-(2-chloro-6-methylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound ClC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C DUPRBTZWZRETAB-UHFFFAOYSA-N 0.000 claims description 3
- LCQHPHJSFITROC-UHFFFAOYSA-N 3-N-(3,5-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC=1C=C(C=C(C=1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C LCQHPHJSFITROC-UHFFFAOYSA-N 0.000 claims description 3
- KVBMASPJHNDSAS-UHFFFAOYSA-N 3-N-(4-fluoro-2,6-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound FC1=CC(=C(C(=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C)C KVBMASPJHNDSAS-UHFFFAOYSA-N 0.000 claims description 3
- TWAJVVGXMJAVHR-UHFFFAOYSA-N 3-N-(4-methoxy-2,6-dimethylphenyl)-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound COC1=CC(=C(C(=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C)C TWAJVVGXMJAVHR-UHFFFAOYSA-N 0.000 claims description 3
- CCBLXCBEHVMOIB-UHFFFAOYSA-N 3-N-[2,6-di(propan-2-yl)phenyl]-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C CCBLXCBEHVMOIB-UHFFFAOYSA-N 0.000 claims description 3
- XFUDHCQIMRDNEM-UHFFFAOYSA-N 3-N-[4-(2-methoxyethoxy)-2,6-dimethylphenyl]-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound COCCOC1=CC(=C(C(=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C)C XFUDHCQIMRDNEM-UHFFFAOYSA-N 0.000 claims description 3
- BLGJNNBVADVKPQ-UHFFFAOYSA-N 3-N-[5-(2-methoxyethoxy)-2-methylphenyl]-1-methyl-6-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound COCCOC=1C=CC(=C(C=1)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C)C BLGJNNBVADVKPQ-UHFFFAOYSA-N 0.000 claims description 3
- ZDIAMSLUQLXBNR-UHFFFAOYSA-N 4-methyl-3-[[1-methyl-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-yl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide Chemical compound CC1=C(C=C(C(=O)NC2=CC(=CC=C2)C(F)(F)F)C=C1)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C ZDIAMSLUQLXBNR-UHFFFAOYSA-N 0.000 claims description 3
- WQVUCJKSZGIMAZ-UHFFFAOYSA-N 6-N-(1,2-dimethyl-3,4-dihydro-1H-isoquinolin-7-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1N(CCC2=CC=C(C=C12)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C)C WQVUCJKSZGIMAZ-UHFFFAOYSA-N 0.000 claims description 3
- SBXQPJJZKCHDPP-UHFFFAOYSA-N 6-N-(3,3-dimethyl-2,4-dihydro-1H-isoquinolin-7-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1(NCC2=CC(=CC=C2C1)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C)C SBXQPJJZKCHDPP-UHFFFAOYSA-N 0.000 claims description 3
- ZCWVKJIXFWOULZ-UHFFFAOYSA-N 6-N-(4,4-dimethyl-2,3-dihydro-1H-isoquinolin-7-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1(CNCC2=CC(=CC=C12)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C)C ZCWVKJIXFWOULZ-UHFFFAOYSA-N 0.000 claims description 3
- MOMSYVYJXVHHGG-UHFFFAOYSA-N 7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNC(C2=C1)=O)C MOMSYVYJXVHHGG-UHFFFAOYSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 3
- SEQNCIBHOCGZIQ-UHFFFAOYSA-N N-[2,4-dimethyl-3-[[1-methyl-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=CC(=C1NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C)C)NC(C1=CC(=CC=C1)C(F)(F)F)=O SEQNCIBHOCGZIQ-UHFFFAOYSA-N 0.000 claims description 3
- JIXZLXVZUQGPCE-UHFFFAOYSA-N N-[3-[[6-[(1,2-dimethyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-1-methylpyrazolo[3,4-d]pyrimidin-3-yl]amino]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1N(CCC2=CC=C(C=C12)NC1=NC=C2C(=N1)N(N=C2NC=1C=C(C=CC=1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C)C JIXZLXVZUQGPCE-UHFFFAOYSA-N 0.000 claims description 3
- HCYMZEKLWNQHQX-UHFFFAOYSA-N N-[3-[[6-[(2-acetyl-1-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-1-methylpyrazolo[3,4-d]pyrimidin-3-yl]amino]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C(C)(=O)N1C(C2=CC(=CC=C2CC1)NC1=NC=C2C(=N1)N(N=C2NC=1C=C(C=CC=1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C)C HCYMZEKLWNQHQX-UHFFFAOYSA-N 0.000 claims description 3
- VJGZAQKDFVLGBN-UHFFFAOYSA-N N-[4-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]prop-2-enamide Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C(C=C1)NC(C=C)=O)C VJGZAQKDFVLGBN-UHFFFAOYSA-N 0.000 claims description 3
- HWMKXUKIQVGAFI-UHFFFAOYSA-N N-[4-methyl-3-[[1-methyl-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C HWMKXUKIQVGAFI-UHFFFAOYSA-N 0.000 claims description 3
- FDSKNGZTTUYPKG-UHFFFAOYSA-N N-[4-methyl-3-[[1-methyl-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]pyridine-2-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(C1=NC=CC=C1)=O)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNCC2=C1)C FDSKNGZTTUYPKG-UHFFFAOYSA-N 0.000 claims description 3
- UZKGRGRBUJXUAY-UHFFFAOYSA-N N-[4-methyl-3-[[1-methyl-6-[(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCNC(C2=C1)C)C UZKGRGRBUJXUAY-UHFFFAOYSA-N 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- QGCNOOPYWYSZAU-UHFFFAOYSA-N cyclopropyl-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]methanone Chemical compound C1(CC1)C(=O)N1CC2=CC(=CC=C2CC1)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C QGCNOOPYWYSZAU-UHFFFAOYSA-N 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- DUJDRMDCCMQERQ-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(1,3,3-trimethyl-2,4-dihydro-1H-isoquinolin-7-yl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CC(NC(C2=C1)C)(C)C)C DUJDRMDCCMQERQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 2
- 208000006678 Abdominal Neoplasms Diseases 0.000 claims description 2
- 208000026872 Addison Disease Diseases 0.000 claims description 2
- 201000004384 Alopecia Diseases 0.000 claims description 2
- 206010061424 Anal cancer Diseases 0.000 claims description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 claims description 2
- 208000007860 Anus Neoplasms Diseases 0.000 claims description 2
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 2
- 208000023328 Basedow disease Diseases 0.000 claims description 2
- 208000009137 Behcet syndrome Diseases 0.000 claims description 2
- 206010004593 Bile duct cancer Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 208000006274 Brain Stem Neoplasms Diseases 0.000 claims description 2
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010010904 Convulsion Diseases 0.000 claims description 2
- 206010058314 Dysplasia Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 201000009273 Endometriosis Diseases 0.000 claims description 2
- 206010014967 Ependymoma Diseases 0.000 claims description 2
- 208000024658 Epilepsy syndrome Diseases 0.000 claims description 2
- 208000002877 Epileptic Syndromes Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 2
- 208000007465 Giant cell arteritis Diseases 0.000 claims description 2
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 2
- 208000015023 Graves' disease Diseases 0.000 claims description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 2
- 206010021042 Hypopharyngeal cancer Diseases 0.000 claims description 2
- 206010056305 Hypopharyngeal neoplasm Diseases 0.000 claims description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010023825 Laryngeal cancer Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000004059 Male Breast Neoplasms Diseases 0.000 claims description 2
- 208000032271 Malignant tumor of penis Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 208000010505 Nose Neoplasms Diseases 0.000 claims description 2
- 201000010133 Oligodendroglioma Diseases 0.000 claims description 2
- 208000003435 Optic Neuritis 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
- 208000002471 Penile Neoplasms Diseases 0.000 claims description 2
- 206010034299 Penile cancer Diseases 0.000 claims description 2
- 201000007286 Pilocytic astrocytoma Diseases 0.000 claims description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims description 2
- 201000005746 Pituitary adenoma Diseases 0.000 claims description 2
- 206010061538 Pituitary tumour benign Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 2
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 208000001106 Takayasu Arteritis Diseases 0.000 claims description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 2
- 208000000728 Thymus Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 231100000360 alopecia Toxicity 0.000 claims description 2
- 206010002224 anaplastic astrocytoma Diseases 0.000 claims description 2
- 201000011165 anus cancer Diseases 0.000 claims description 2
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 2
- 230000002567 autonomic effect Effects 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 2
- 230000007882 cirrhosis Effects 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 230000001079 digestive effect Effects 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 201000002491 encephalomyelitis Diseases 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 206010016256 fatigue Diseases 0.000 claims description 2
- 201000000374 female urethral cancer Diseases 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 230000002710 gonadal effect Effects 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 201000006866 hypopharynx cancer Diseases 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 238000007917 intracranial administration Methods 0.000 claims description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 201000003175 male breast cancer Diseases 0.000 claims description 2
- 208000010907 male breast carcinoma Diseases 0.000 claims description 2
- 208000030883 malignant astrocytoma Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000000349 mediastinal cancer Diseases 0.000 claims description 2
- 206010027191 meningioma Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 206010028417 myasthenia gravis Diseases 0.000 claims description 2
- VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 2
- 208000037830 nasal cancer Diseases 0.000 claims description 2
- 208000018280 neoplasm of mediastinum Diseases 0.000 claims description 2
- 208000025426 neoplasm of thorax Diseases 0.000 claims description 2
- 230000002232 neuromuscular Effects 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 206010029864 nystagmus Diseases 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 208000021310 pituitary gland adenoma Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 230000009885 systemic effect Effects 0.000 claims description 2
- 206010043207 temporal arteritis Diseases 0.000 claims description 2
- 201000003957 thoracic cancer Diseases 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 208000037965 uterine sarcoma Diseases 0.000 claims description 2
- 201000008073 uveal cancer Diseases 0.000 claims description 2
- 206010046885 vaginal cancer Diseases 0.000 claims description 2
- 208000013139 vaginal neoplasm Diseases 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 343
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 201
- 238000005160 1H NMR spectroscopy Methods 0.000 description 196
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 172
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 168
- 239000000243 solution Substances 0.000 description 105
- 239000011541 reaction mixture Substances 0.000 description 101
- 230000002829 reductive effect Effects 0.000 description 87
- 235000019439 ethyl acetate Nutrition 0.000 description 85
- 239000012044 organic layer Substances 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 64
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 239000012043 crude product Substances 0.000 description 54
- 229910052938 sodium sulfate Inorganic materials 0.000 description 54
- 238000004440 column chromatography Methods 0.000 description 53
- 238000003756 stirring Methods 0.000 description 52
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 40
- 238000000605 extraction Methods 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 239000003480 eluent Substances 0.000 description 30
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- 238000010898 silica gel chromatography Methods 0.000 description 28
- 239000002904 solvent Substances 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 239000007832 Na2SO4 Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 239000007858 starting material Substances 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 14
- TWEVSIDPSZLIFY-UHFFFAOYSA-N 1-(7-amino-1,3,3-trimethyl-1,4-dihydroisoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C2CC(N(C(C2=C1)C)C(C(F)(F)F)=O)(C)C TWEVSIDPSZLIFY-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 235000013361 beverage Nutrition 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- PJIRPGOFEWFXSD-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,3,3-trimethyl-1,4-dihydroisoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CC(N(C(C2=C1)C)C(C(F)(F)F)=O)(C)C)C PJIRPGOFEWFXSD-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- FHWYREZXHZHYGA-UHFFFAOYSA-N 2,4-dichloro-n-(2,6-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CN=C(Cl)N=C1Cl FHWYREZXHZHYGA-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- DZTIFMWYYHCREC-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carbonyl chloride Chemical compound ClC(=O)C1=CN=C(Cl)N=C1Cl DZTIFMWYYHCREC-UHFFFAOYSA-N 0.000 description 6
- VMUFUDJPUMSUMP-UHFFFAOYSA-N 6-chloro-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C VMUFUDJPUMSUMP-UHFFFAOYSA-N 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- PDNRNWDJXTYDNZ-UHFFFAOYSA-N 2,2,2-trifluoro-1-(1,3,3-trimethyl-7-nitro-1,4-dihydroisoquinolin-2-yl)ethanone Chemical compound FC(C(=O)N1C(C2=CC(=CC=C2CC1(C)C)[N+](=O)[O-])C)(F)F PDNRNWDJXTYDNZ-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000019634 flavors Nutrition 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- LKBRDOYIPKDONZ-UHFFFAOYSA-N 1-(6-amino-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound NC=1C=C2CCN(CC2=CC=1OC)C(C(F)(F)F)=O LKBRDOYIPKDONZ-UHFFFAOYSA-N 0.000 description 4
- HHMKKMHCANDEEH-UHFFFAOYSA-N 1-(7-amino-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C2CCN(C(C2=C1)(C)C)C(C(F)(F)F)=O HHMKKMHCANDEEH-UHFFFAOYSA-N 0.000 description 4
- YEZPCNZZDHCZDL-UHFFFAOYSA-N 1-(7-amino-3,4-dihydro-1h-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound C1CN(C(=O)C(F)(F)F)CC2=CC(N)=CC=C21 YEZPCNZZDHCZDL-UHFFFAOYSA-N 0.000 description 4
- ABKUFIFLYLVADX-UHFFFAOYSA-N 1-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine Chemical compound C1=C(N)C=C2C(C)NCCC2=C1 ABKUFIFLYLVADX-UHFFFAOYSA-N 0.000 description 4
- DICQLPHFSUDSCU-UHFFFAOYSA-N 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-7-nitro-3,4-dihydroisoquinolin-2-yl)ethanone Chemical compound FC(C(=O)N1C(C2=CC(=C(C=C2CC1)OC)[N+](=O)[O-])(C)C)(F)F DICQLPHFSUDSCU-UHFFFAOYSA-N 0.000 description 4
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 4
- NUNAWQZKZVVELQ-UHFFFAOYSA-N 3-amino-4-methylphenol Chemical compound CC1=CC=C(O)C=C1N NUNAWQZKZVVELQ-UHFFFAOYSA-N 0.000 description 4
- ZQXHLFFOROUKTJ-UHFFFAOYSA-N 5-(2-methoxyethoxy)-2-methylaniline Chemical compound COCCOC1=CC=C(C)C(N)=C1 ZQXHLFFOROUKTJ-UHFFFAOYSA-N 0.000 description 4
- 229910004373 HOAc Inorganic materials 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 108700012920 TNF Proteins 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000306 component Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 235000013402 health food Nutrition 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 239000010802 sludge Substances 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- HFNOAVXTUXLYNM-UHFFFAOYSA-N 1,3,3-trimethyl-4h-isoquinoline Chemical compound C1=CC=C2C(C)=NC(C)(C)CC2=C1 HFNOAVXTUXLYNM-UHFFFAOYSA-N 0.000 description 3
- JPJJJRGPSZULTC-UHFFFAOYSA-N 1,3,3-trimethyl-7-nitro-4h-isoquinoline Chemical compound C1=C([N+]([O-])=O)C=C2C(C)=NC(C)(C)CC2=C1 JPJJJRGPSZULTC-UHFFFAOYSA-N 0.000 description 3
- UTDBLNFAKUZGNT-UHFFFAOYSA-N 1-(6-amino-3,4-dihydro-1h-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound C1N(C(=O)C(F)(F)F)CCC2=CC(N)=CC=C21 UTDBLNFAKUZGNT-UHFFFAOYSA-N 0.000 description 3
- ZKSHVQYGKMDTFX-UHFFFAOYSA-N 1-(7-amino-1-propan-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C2CCN(C(C2=C1)C(C)C)C(C(F)(F)F)=O ZKSHVQYGKMDTFX-UHFFFAOYSA-N 0.000 description 3
- XWVFMJLNNGXNSG-UHFFFAOYSA-N 1-(7-amino-3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound C1=C(N)C=C2CN(C(=O)C)CCC2=C1 XWVFMJLNNGXNSG-UHFFFAOYSA-N 0.000 description 3
- AKLFDWPAHMQRTO-UHFFFAOYSA-N 1-[3-[(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)amino]-4-methylphenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC=1C=C(C=CC=1C)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)C AKLFDWPAHMQRTO-UHFFFAOYSA-N 0.000 description 3
- LOWUXJROLYOIDB-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(C(C2=C1)(C)C)C(C(F)(F)F)=O)C LOWUXJROLYOIDB-UHFFFAOYSA-N 0.000 description 3
- XKYKHNOGUWIVSV-UHFFFAOYSA-N 2,2,2-trifluoro-1-(5-nitro-1,3-dihydroisoindol-2-yl)ethanone Chemical compound [O-][N+](=O)C1=CC=C2CN(C(=O)C(F)(F)F)CC2=C1 XKYKHNOGUWIVSV-UHFFFAOYSA-N 0.000 description 3
- VQJCJKZEKUVZEX-UHFFFAOYSA-N 2,2,2-trifluoro-1-(6-hydroxy-1,1-dimethyl-7-nitro-3,4-dihydroisoquinolin-2-yl)ethanone Chemical compound FC(C(=O)N1C(C2=CC(=C(C=C2CC1)O)[N+](=O)[O-])(C)C)(F)F VQJCJKZEKUVZEX-UHFFFAOYSA-N 0.000 description 3
- QPVAIUABDRELMS-UHFFFAOYSA-N 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl)ethanone Chemical compound FC(C(=O)N1C(C2=CC=C(C=C2CC1)OC)(C)C)(F)F QPVAIUABDRELMS-UHFFFAOYSA-N 0.000 description 3
- ARDYHOMYWMROCB-UHFFFAOYSA-N 2,4-dichloro-n-(2,6-dichlorophenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC(Cl)=NC=C1C(=O)NC1=C(Cl)C=CC=C1Cl ARDYHOMYWMROCB-UHFFFAOYSA-N 0.000 description 3
- ALKDJYVTIUINTL-UHFFFAOYSA-N 2,4-dichloro-n-phenylpyrimidine-5-carboxamide Chemical compound ClC1=NC(Cl)=NC=C1C(=O)NC1=CC=CC=C1 ALKDJYVTIUINTL-UHFFFAOYSA-N 0.000 description 3
- GGJUSGFZOUPGDI-UHFFFAOYSA-N 3,4-dihydro-1h-isochromen-7-amine Chemical compound C1COCC2=CC(N)=CC=C21 GGJUSGFZOUPGDI-UHFFFAOYSA-N 0.000 description 3
- RAYDHJRWEQYFPK-UHFFFAOYSA-N 4-[amino(cyclohexyl)amino]-2-chloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C1CCCCC1)C(=O)NC1=C(C=CC=C1C)C RAYDHJRWEQYFPK-UHFFFAOYSA-N 0.000 description 3
- SULGEJSSAVKYGW-UHFFFAOYSA-N 4-[amino(cyclopentyl)amino]-2-chloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C1CCCC1)C(=O)NC1=C(C=CC=C1C)C SULGEJSSAVKYGW-UHFFFAOYSA-N 0.000 description 3
- PBEPLBGVNIYAHM-UHFFFAOYSA-N 4-[amino(methyl)amino]-2-chloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C)C(=O)NC1=C(C=CC=C1Cl)Cl PBEPLBGVNIYAHM-UHFFFAOYSA-N 0.000 description 3
- DAPSRVWACOXHMM-UHFFFAOYSA-N 4-[amino(methyl)amino]-2-chloro-N-(3,5-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C)C(=O)NC1=CC(=CC(=C1)C)C DAPSRVWACOXHMM-UHFFFAOYSA-N 0.000 description 3
- ZQVSPFWBJHWTDP-UHFFFAOYSA-N 4-[amino(methyl)amino]-2-chloro-N-phenylpyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C)C(=O)NC1=CC=CC=C1 ZQVSPFWBJHWTDP-UHFFFAOYSA-N 0.000 description 3
- XSRPITUMHPXHEA-UHFFFAOYSA-N 4-[amino(propan-2-yl)amino]-2-chloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C(C)C)C(=O)NC1=C(C=CC=C1C)C XSRPITUMHPXHEA-UHFFFAOYSA-N 0.000 description 3
- XJZBAGXKIKKRKG-UHFFFAOYSA-N 6-chloro-1-cyclohexyl-N-(2,6-dimethylphenyl)pyrazolo[3,4-d]pyrimidin-3-amine Chemical compound Cc1cccc(C)c1Nc1nn(C2CCCCC2)c2nc(Cl)ncc12 XJZBAGXKIKKRKG-UHFFFAOYSA-N 0.000 description 3
- HXHLLGFFPIRNNB-UHFFFAOYSA-N 6-chloro-1-cyclopentyl-N-(2,6-dimethylphenyl)pyrazolo[3,4-d]pyrimidin-3-amine Chemical compound Cc1cccc(C)c1Nc1nn(C2CCCC2)c2nc(Cl)ncc12 HXHLLGFFPIRNNB-UHFFFAOYSA-N 0.000 description 3
- ZULNOCZJFXVCCU-UHFFFAOYSA-N 6-chloro-1-methyl-N-phenylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=CC=CC=C1)C ZULNOCZJFXVCCU-UHFFFAOYSA-N 0.000 description 3
- GXTSYNFFKMDDEF-UHFFFAOYSA-N 6-chloro-N-(2,6-dichlorophenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1Cl)Cl)C GXTSYNFFKMDDEF-UHFFFAOYSA-N 0.000 description 3
- YCQAMQXZGAHIAK-UHFFFAOYSA-N 6-chloro-N-(2,6-dimethylphenyl)-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)C)C(C)C YCQAMQXZGAHIAK-UHFFFAOYSA-N 0.000 description 3
- DTYXQCRCZNHNPI-UHFFFAOYSA-N 6-chloro-N-(2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)NN=C2NC1=C(C=CC=C1C)C DTYXQCRCZNHNPI-UHFFFAOYSA-N 0.000 description 3
- VGPXTUJWBIIVOI-UHFFFAOYSA-N 6-chloro-N-(2-chloro-3,5-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C(=CC(=C1)C)C)Cl)C VGPXTUJWBIIVOI-UHFFFAOYSA-N 0.000 description 3
- QJSWPNBVJSANQK-UHFFFAOYSA-N 7-nitro-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1CNC(=O)C2=CC([N+](=O)[O-])=CC=C21 QJSWPNBVJSANQK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229940124291 BTK inhibitor Drugs 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910019213 POCl3 Inorganic materials 0.000 description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 3
- WTZMGALEPUUHMT-UHFFFAOYSA-N [1,1-dimethyl-7-nitro-2-(2,2,2-trifluoroacetyl)-3,4-dihydroisoquinolin-6-yl] trifluoromethanesulfonate Chemical compound FC(S(=O)(=O)OC=1C=C2CCN(C(C2=CC=1[N+](=O)[O-])(C)C)C(C(F)(F)F)=O)(F)F WTZMGALEPUUHMT-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- WNVPACYPJUPHON-UHFFFAOYSA-N n-(4-aminophenyl)prop-2-enamide Chemical compound NC1=CC=C(NC(=O)C=C)C=C1 WNVPACYPJUPHON-UHFFFAOYSA-N 0.000 description 3
- DFKKBOJXPCXEGX-UHFFFAOYSA-N n-(4-nitrophenyl)prop-2-enamide Chemical compound [O-][N+](=O)C1=CC=C(NC(=O)C=C)C=C1 DFKKBOJXPCXEGX-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000011368 organic material Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000004323 potassium nitrate Substances 0.000 description 3
- 235000010333 potassium nitrate Nutrition 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- QWPSFDIZENOWIK-UHFFFAOYSA-N tert-butyl N-[[2-chloro-5-[(2,6-dimethylphenyl)carbamoyl]pyrimidin-4-yl]amino]carbamate Chemical compound C(C)(C)(C)OC(=O)NNC1=NC(=NC=C1C(NC1=C(C=CC=C1C)C)=O)Cl QWPSFDIZENOWIK-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 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
- 210000004881 tumor cell Anatomy 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SEEVTOSNSHJITE-UHFFFAOYSA-N 1-(4,4-dimethyl-7-nitro-1,3-dihydroisoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound [O-][N+](=O)C1=CC=C2C(C)(C)CN(C(=O)C(F)(F)F)CC2=C1 SEEVTOSNSHJITE-UHFFFAOYSA-N 0.000 description 2
- GLZWTOBGMDMQCW-UHFFFAOYSA-N 1-(5-amino-1,3-dihydroisoindol-2-yl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C2CN(C(=O)C(F)(F)F)CC2=C1 GLZWTOBGMDMQCW-UHFFFAOYSA-N 0.000 description 2
- BCTSXRBQKANWHM-UHFFFAOYSA-N 1-(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)-6-methylcyclohexa-3,5-diene-1,3-diamine Chemical compound ClC1=NC=C2C(=N1)N(N=C2C1(CC(=CC=C1C)N)N)C BCTSXRBQKANWHM-UHFFFAOYSA-N 0.000 description 2
- VPZDAXKLFBENRE-UHFFFAOYSA-N 1-(7-amino-4,4-dimethyl-1,3-dihydroisoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C2C(C)(C)CN(C(=O)C(F)(F)F)CC2=C1 VPZDAXKLFBENRE-UHFFFAOYSA-N 0.000 description 2
- VKQVUQYZTXGZLW-UHFFFAOYSA-N 1-(7-bromo-3,4-dihydro-1h-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound C1=C(Br)C=C2CN(C(=O)C(F)(F)F)CCC2=C1 VKQVUQYZTXGZLW-UHFFFAOYSA-N 0.000 description 2
- ZDVBRUOONPLBFS-UHFFFAOYSA-N 1-(7-bromo-6-nitro-3,4-dihydro-1h-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound C1CN(C(=O)C(F)(F)F)CC2=C1C=C([N+](=O)[O-])C(Br)=C2 ZDVBRUOONPLBFS-UHFFFAOYSA-N 0.000 description 2
- BKJRHIYYEKJYTP-UHFFFAOYSA-N 1-(7-nitro-3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound C1=C([N+]([O-])=O)C=C2CN(C(=O)C)CCC2=C1 BKJRHIYYEKJYTP-UHFFFAOYSA-N 0.000 description 2
- SAKWWOWDBOSATE-UHFFFAOYSA-N 1-[4-[4-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperidin-1-yl]ethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C(C=C1)C1CCN(CC1)C(C)=O)C SAKWWOWDBOSATE-UHFFFAOYSA-N 0.000 description 2
- JLQGNJWCJLMWNJ-UHFFFAOYSA-N 1-[4-methyl-3-[[1-methyl-6-[[2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinolin-7-yl]amino]pyrazolo[3,4-d]pyrimidin-3-yl]amino]phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound CC1=C(C=C(C=C1)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)NC1=NN(C2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C(F)(F)F)=O)C JLQGNJWCJLMWNJ-UHFFFAOYSA-N 0.000 description 2
- UYGFDZVPJHPVRR-UHFFFAOYSA-N 1-[5-[[3-(2,6-dimethylanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,3-dihydroisoindol-2-yl]-2,2,2-trifluoroethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CN(CC2=CC=1)C(C(F)(F)F)=O)C UYGFDZVPJHPVRR-UHFFFAOYSA-N 0.000 description 2
- UUJZSFDTGQRZDH-UHFFFAOYSA-N 1-propan-2-yl-3,4-dihydroisoquinoline Chemical compound C1=CC=C2C(C(C)C)=NCCC2=C1 UUJZSFDTGQRZDH-UHFFFAOYSA-N 0.000 description 2
- OBBGVDVUAMAJFQ-UHFFFAOYSA-N 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-5-nitro-3,4-dihydroisoquinolin-2-yl)ethanone Chemical compound FC(C(=O)N1C(C2=CC=C(C(=C2CC1)[N+](=O)[O-])OC)(C)C)(F)F OBBGVDVUAMAJFQ-UHFFFAOYSA-N 0.000 description 2
- JBIBCOWGRGJAAV-UHFFFAOYSA-N 2,2,2-trifluoro-1-(7-nitro-1-propan-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone Chemical compound FC(C(=O)N1C(C2=CC(=CC=C2CC1)[N+](=O)[O-])C(C)C)(F)F JBIBCOWGRGJAAV-UHFFFAOYSA-N 0.000 description 2
- QNZQGGKAGPRZEE-UHFFFAOYSA-N 2,2,2-trifluoro-1-(7-nitro-3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound C1CN(C(=O)C(F)(F)F)CC2=CC([N+](=O)[O-])=CC=C21 QNZQGGKAGPRZEE-UHFFFAOYSA-N 0.000 description 2
- UOSQIKVRERBVOD-UHFFFAOYSA-N 2,2,2-trifluoro-1-[7-[[3-[4-(2-methoxyethoxy)-2,6-dimethylanilino]-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1,1-dimethyl-3,4-dihydroisoquinolin-2-yl]ethanone Chemical compound FC(C(=O)N1C(C2=CC(=CC=C2CC1)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OCCOC)C)C)(C)C)(F)F UOSQIKVRERBVOD-UHFFFAOYSA-N 0.000 description 2
- NZJHTQHPPRUEGB-UHFFFAOYSA-N 2,2,2-trifluoro-1-[7-[[3-[4-(2-methoxyethoxy)-2,6-dimethylanilino]-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-1-propan-2-yl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Chemical compound FC(C(=O)N1C(C2=CC(=CC=C2CC1)NC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OCCOC)C)C)C(C)C)(F)F NZJHTQHPPRUEGB-UHFFFAOYSA-N 0.000 description 2
- QLPXLXCSOYUXRI-UHFFFAOYSA-N 2,2,2-trifluoro-n-[2-methyl-2-(4-nitrophenyl)propyl]acetamide Chemical compound FC(F)(F)C(=O)NCC(C)(C)C1=CC=C([N+]([O-])=O)C=C1 QLPXLXCSOYUXRI-UHFFFAOYSA-N 0.000 description 2
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- VOWZNBNDMFLQGM-UHFFFAOYSA-N 2,5-dimethylaniline Chemical compound CC1=CC=C(C)C(N)=C1 VOWZNBNDMFLQGM-UHFFFAOYSA-N 0.000 description 2
- QVFONYRRUSRIBT-UHFFFAOYSA-N 2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-5-nitrobenzoic acid Chemical compound C(C)OC(C(C(=O)OCC)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-])=O QVFONYRRUSRIBT-UHFFFAOYSA-N 0.000 description 2
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 2
- QHIFWNXJOHQQTH-UHFFFAOYSA-N 2-(carboxymethyl)-5-nitrobenzoic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1C(O)=O QHIFWNXJOHQQTH-UHFFFAOYSA-N 0.000 description 2
- LHYRRHWYOPLOBK-UHFFFAOYSA-N 2-[2-(hydroxymethyl)-4-nitrophenyl]ethanol Chemical compound OCCC1=CC=C([N+]([O-])=O)C=C1CO LHYRRHWYOPLOBK-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- XZVURMRLCAFELZ-UHFFFAOYSA-N 2-methyl-2-(4-nitrophenyl)propanenitrile Chemical compound N#CC(C)(C)C1=CC=C([N+]([O-])=O)C=C1 XZVURMRLCAFELZ-UHFFFAOYSA-N 0.000 description 2
- MYJFFRMEBNWEQO-UHFFFAOYSA-N 2-methyl-n-(2-phenylethyl)propan-1-amine Chemical compound CC(C)CNCCC1=CC=CC=C1 MYJFFRMEBNWEQO-UHFFFAOYSA-N 0.000 description 2
- RDUHDSUWMQEJLP-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-1-methyl-6-N-(4-piperidin-4-ylphenyl)pyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1=C(C(=CC=C1)C)NC1=NN(C2=NC(=NC=C21)NC1=CC=C(C=C1)C1CCNCC1)C RDUHDSUWMQEJLP-UHFFFAOYSA-N 0.000 description 2
- ATWIAMBYXKGGFA-UHFFFAOYSA-N 3-N-(2,6-dimethylphenyl)-6-N-(1,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound CC1CC2=CC=C(NC3=NC=C4C(NC5=C(C)C=CC=C5C)=NN(C)C4=N3)C=C2C(C)N1 ATWIAMBYXKGGFA-UHFFFAOYSA-N 0.000 description 2
- GYFGDBWFBQUHLB-UHFFFAOYSA-N 3-N-(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)-4-methylbenzene-1,3-diamine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=CC(=CC=C1C)N)C GYFGDBWFBQUHLB-UHFFFAOYSA-N 0.000 description 2
- NGBITBZUGNGLLZ-UHFFFAOYSA-N 3-[(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)amino]-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC=1C=C(C(=O)NC2=CC(=CC=C2)C(F)(F)F)C=CC=1C)C NGBITBZUGNGLLZ-UHFFFAOYSA-N 0.000 description 2
- LMDKWXRADXWSIQ-UHFFFAOYSA-N 4-(2-methoxyethoxy)-2,6-dimethylaniline Chemical compound COCCOC1=CC(C)=C(N)C(C)=C1 LMDKWXRADXWSIQ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- KHZLBPQVQFBVLH-UHFFFAOYSA-N 4-[(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)amino]-3,5-dimethyl-N-pyridin-2-ylbenzamide Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C(=O)NC2=NC=CC=C2)C=C1C)C)C KHZLBPQVQFBVLH-UHFFFAOYSA-N 0.000 description 2
- WXYKEZKCMNYHMH-UHFFFAOYSA-N 4-amino-3,5-dimethyl-N-pyridin-2-ylbenzamide Chemical compound NC1=C(C=C(C(=O)NC2=NC=CC=C2)C=C1C)C WXYKEZKCMNYHMH-UHFFFAOYSA-N 0.000 description 2
- GCWYXRHXGLFVFE-UHFFFAOYSA-N 4-hydroxy-2,6-dimethylaniline Chemical compound CC1=CC(O)=CC(C)=C1N GCWYXRHXGLFVFE-UHFFFAOYSA-N 0.000 description 2
- XFMUCDRJXZLSNE-UHFFFAOYSA-N 4-methoxy-2,6-dimethylaniline Chemical compound COC1=CC(C)=C(N)C(C)=C1 XFMUCDRJXZLSNE-UHFFFAOYSA-N 0.000 description 2
- DNNGLKODJQTXEY-UHFFFAOYSA-N 6-chloro-1-methyl-N-(2-methyl-5-nitrophenyl)pyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC(=C1)[N+](=O)[O-])C)C DNNGLKODJQTXEY-UHFFFAOYSA-N 0.000 description 2
- VJUNXTNKSMUCQV-UHFFFAOYSA-N 6-chloro-N-(4-methoxy-2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OC)C)C VJUNXTNKSMUCQV-UHFFFAOYSA-N 0.000 description 2
- WLJOQEOBPDNSHE-UHFFFAOYSA-N 6-chloro-N-[4-(2-methoxyethoxy)-2,6-dimethylphenyl]-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OCCOC)C)C WLJOQEOBPDNSHE-UHFFFAOYSA-N 0.000 description 2
- REOWQNQYVBJKJF-UHFFFAOYSA-N 6-chloro-N-[5-(2-methoxyethoxy)-2-methylphenyl]-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC(=C1)OCCOC)C)C REOWQNQYVBJKJF-UHFFFAOYSA-N 0.000 description 2
- VNUQVKZHEBCTNT-UHFFFAOYSA-N 7-amino-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1CNC(=O)C2=CC(N)=CC=C21 VNUQVKZHEBCTNT-UHFFFAOYSA-N 0.000 description 2
- FRHKNGAGKAEVOO-UHFFFAOYSA-N 7-methoxy-1-methyl-3,4-dihydroisoquinoline Chemical compound C1CN=C(C)C2=CC(OC)=CC=C21 FRHKNGAGKAEVOO-UHFFFAOYSA-N 0.000 description 2
- MXZSKXWXUGTGOE-UHFFFAOYSA-N 7-nitro-1-propan-2-yl-3,4-dihydroisoquinoline Chemical compound C1=C([N+]([O-])=O)C=C2C(C(C)C)=NCCC2=C1 MXZSKXWXUGTGOE-UHFFFAOYSA-N 0.000 description 2
- YGESIJUSNLKASY-UHFFFAOYSA-N 7-nitro-3,4-dihydro-1h-isochromene Chemical compound C1COCC2=CC([N+](=O)[O-])=CC=C21 YGESIJUSNLKASY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 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
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000004606 Fillers/Extenders Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 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
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- PBQSOEVROSGZFY-UHFFFAOYSA-N N-(3-amino-2,4-dimethylphenyl)-3-(trifluoromethyl)benzamide Chemical compound NC=1C(=C(C=CC=1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C PBQSOEVROSGZFY-UHFFFAOYSA-N 0.000 description 2
- QZFROFRYGXPYMQ-UHFFFAOYSA-N N-(4-bromo-4-ethoxycyclohexa-1,5-dien-1-yl)-2,2,2-trifluoroacetamide Chemical compound BrC1(CC=C(C=C1)NC(C(F)(F)F)=O)OCC QZFROFRYGXPYMQ-UHFFFAOYSA-N 0.000 description 2
- PLAHJWPQTBXQCQ-UHFFFAOYSA-N N-(4-ethoxy-4-methoxycyclohexa-1,5-dien-1-yl)acetamide Chemical compound COC1(CC=C(C=C1)NC(C)=O)OCC PLAHJWPQTBXQCQ-UHFFFAOYSA-N 0.000 description 2
- FCOCLMFOVXAWQH-UHFFFAOYSA-N N-(4-ethoxy-4-nitrocyclohexa-1,5-dien-1-yl)-2,2,2-trifluoroacetamide Chemical compound FC(C(=O)NC1=CCC(C=C1)(OCC)[N+](=O)[O-])(F)F FCOCLMFOVXAWQH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PLPPYIZFTSUCOL-UHFFFAOYSA-N N-[3-[(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)amino]-2,4-dimethylphenyl]-3-(trifluoromethyl)benzamide Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC=1C(=C(C=CC=1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C)C PLPPYIZFTSUCOL-UHFFFAOYSA-N 0.000 description 2
- VEVDQIZPZONUNX-UHFFFAOYSA-N N-[3-[(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)amino]-4-methylphenyl]pyridine-2-carboxamide Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC=1C=C(C=CC=1C)NC(C1=NC=CC=C1)=O)C VEVDQIZPZONUNX-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Chemical class 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003181 biological factor Substances 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 108010075324 emt protein-tyrosine kinase Proteins 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229940041476 lactose 100 mg Drugs 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- MWVNSIAUXRLDHJ-UHFFFAOYSA-N n-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1NC(=O)C1=CC=CC(C(F)(F)F)=C1 MWVNSIAUXRLDHJ-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229940127084 other anti-cancer agent Drugs 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000004526 pharmaceutical effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000013037 reversible inhibitor Substances 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ZXYAAVBXHKCJJB-UHFFFAOYSA-N uracil-5-carboxylic acid Chemical compound OC(=O)C1=CNC(=O)NC1=O ZXYAAVBXHKCJJB-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- XUUSVHGZGPBZLS-UHFFFAOYSA-N 1,3-dimethyl-2,4-dinitrobenzene Chemical compound CC1=CC=C([N+]([O-])=O)C(C)=C1[N+]([O-])=O XUUSVHGZGPBZLS-UHFFFAOYSA-N 0.000 description 1
- HDFQKJQEWGVKCQ-UHFFFAOYSA-N 1,3-dimethyl-2-nitrobenzene Chemical compound CC1=CC=CC(C)=C1[N+]([O-])=O HDFQKJQEWGVKCQ-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- VKRKCBWIVLSRBJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-one Chemical compound C1CC(=O)CCC21OCCO2 VKRKCBWIVLSRBJ-UHFFFAOYSA-N 0.000 description 1
- JWJCOMFXOMVIEQ-UHFFFAOYSA-N 1-(7-amino-4,4-dimethyl-2,3-dihydro-1H-quinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C2C(CC(NC2=C1)C(C(F)(F)F)=O)(C)C JWJCOMFXOMVIEQ-UHFFFAOYSA-N 0.000 description 1
- ZXYUUQBMIVRZNT-UHFFFAOYSA-N 1-[6-[[3-(2,6-dichloroanilino)-1-methylpyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound ClC1=C(C(=CC=C1)Cl)NC1=NN(C2=NC(=NC=C21)NC=1C=C2CCN(CC2=CC=1)C(C(F)(F)F)=O)C ZXYUUQBMIVRZNT-UHFFFAOYSA-N 0.000 description 1
- RZAWDEBNJDYQAZ-UHFFFAOYSA-N 1-[7-[[3-(2,6-dimethylanilino)-2H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone Chemical compound CC1=C(C(=CC=C1)C)NC1=NNC2=NC(=NC=C21)NC1=CC=C2CCN(CC2=C1)C(C(F)(F)F)=O RZAWDEBNJDYQAZ-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- ZDFBKZUDCQQKAC-UHFFFAOYSA-N 1-bromo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1 ZDFBKZUDCQQKAC-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- SXJYSIBLFGQAND-UHFFFAOYSA-N 1-isocyanato-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(N=C=O)=C1 SXJYSIBLFGQAND-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- ZPDPRPHPYMTWMA-UHFFFAOYSA-N 2,4-di(propan-2-yl)aniline Chemical compound CC(C)C1=CC=C(N)C(C(C)C)=C1 ZPDPRPHPYMTWMA-UHFFFAOYSA-N 0.000 description 1
- ROXHGHHFXJVSTN-UHFFFAOYSA-N 2,4-dichloro-N-(3,5-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)Cl)C(=O)NC1=CC(=CC(=C1)C)C ROXHGHHFXJVSTN-UHFFFAOYSA-N 0.000 description 1
- HOSJCFMDVCGSQM-UHFFFAOYSA-N 2,4-diethylaniline Chemical compound CCC1=CC=C(N)C(CC)=C1 HOSJCFMDVCGSQM-UHFFFAOYSA-N 0.000 description 1
- MCRYBELDVGNCFW-UHFFFAOYSA-N 2,4-dimethyl-3-nitroaniline Chemical compound CC1=CC=C(N)C(C)=C1[N+]([O-])=O MCRYBELDVGNCFW-UHFFFAOYSA-N 0.000 description 1
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 1
- ODUZJBKKYBQIBX-UHFFFAOYSA-N 2,6-difluoroaniline Chemical compound NC1=C(F)C=CC=C1F ODUZJBKKYBQIBX-UHFFFAOYSA-N 0.000 description 1
- HQBJSEKQNRSDAZ-UHFFFAOYSA-N 2,6-dimethoxyaniline Chemical compound COC1=CC=CC(OC)=C1N HQBJSEKQNRSDAZ-UHFFFAOYSA-N 0.000 description 1
- WJBMRZAHTUFBGE-UHFFFAOYSA-N 2-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1 WJBMRZAHTUFBGE-UHFFFAOYSA-N 0.000 description 1
- ZSZCXAOQVBEPME-UHFFFAOYSA-N 2-(4-bromophenyl)ethanamine Chemical compound NCCC1=CC=C(Br)C=C1 ZSZCXAOQVBEPME-UHFFFAOYSA-N 0.000 description 1
- PXNJGLAVKOXITN-UHFFFAOYSA-N 2-(4-nitrophenyl)acetonitrile Chemical compound [O-][N+](=O)C1=CC=C(CC#N)C=C1 PXNJGLAVKOXITN-UHFFFAOYSA-N 0.000 description 1
- LQFVLMDZLYAFFW-UHFFFAOYSA-N 2-benzyl-6-methoxy-1,1-dimethyl-3,4-dihydroisoquinoline Chemical compound C(C1=CC=CC=C1)N1C(C2=CC=C(C=C2CC1)OC)(C)C LQFVLMDZLYAFFW-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- QUEKGYQTRJVEQC-UHFFFAOYSA-N 2516-96-3 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-N 0.000 description 1
- YISDQRBVKTUQAK-UHFFFAOYSA-N 3,3-dimethyl-2,4-dihydro-1H-isoquinolin-7-amine Chemical compound CC1(NCC2=CC(=CC=C2C1)N)C YISDQRBVKTUQAK-UHFFFAOYSA-N 0.000 description 1
- YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 description 1
- YBEQJNHDQZFIIM-UHFFFAOYSA-N 3,5-dimethyl-4-nitro-N-pyridin-2-ylbenzamide Chemical compound CC=1C=C(C(=O)NC2=NC=CC=C2)C=C(C=1[N+](=O)[O-])C YBEQJNHDQZFIIM-UHFFFAOYSA-N 0.000 description 1
- RBAVFNOGEPCOQI-UHFFFAOYSA-N 3,5-dimethyl-4-nitrobenzoic acid Chemical compound CC1=CC(C(O)=O)=CC(C)=C1[N+]([O-])=O RBAVFNOGEPCOQI-UHFFFAOYSA-N 0.000 description 1
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 1
- RUJYJCANMOTJMO-UHFFFAOYSA-N 3-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC(C(Cl)=O)=C1 RUJYJCANMOTJMO-UHFFFAOYSA-N 0.000 description 1
- XKFIFYROMAAUDL-UHFFFAOYSA-N 3-amino-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1N XKFIFYROMAAUDL-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
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- MXLMTQWGSQIYOW-UHFFFAOYSA-N 3-methyl-2-butanol Chemical compound CC(C)C(C)O MXLMTQWGSQIYOW-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- ICGJMOQIBHOGER-UHFFFAOYSA-N 4-[amino(methyl)amino]-2-chloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N(N)C)C(=O)NC1=C(C=CC=C1C)C ICGJMOQIBHOGER-UHFFFAOYSA-N 0.000 description 1
- YFSLBELJYPLIHB-UHFFFAOYSA-N 4-fluoro-2,5-dimethylaniline Chemical compound CC1=CC(F)=C(C)C=C1N YFSLBELJYPLIHB-UHFFFAOYSA-N 0.000 description 1
- BQEXDUKMTVYBRK-UHFFFAOYSA-N 4-methyl-3-nitrophenol Chemical compound CC1=CC=C(O)C=C1[N+]([O-])=O BQEXDUKMTVYBRK-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- MOXOFSFWYLTCFU-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-2-amine Chemical compound C1CCCC2=CC(N)=CC=C21 MOXOFSFWYLTCFU-UHFFFAOYSA-N 0.000 description 1
- BAVCONABVFUKDM-UHFFFAOYSA-N 6-N-(2,3-dihydro-1H-isoindol-5-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine Chemical compound Cc1cccc(C)c1Nc1nn(C)c2nc(Nc3ccc4CNCc4c3)ncc12 BAVCONABVFUKDM-UHFFFAOYSA-N 0.000 description 1
- HPGKDPKCOGXQNZ-UHFFFAOYSA-N 6-N-(2,3-dihydro-1H-isoindol-5-yl)-3-N-(2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride Chemical compound Cl.Cc1cccc(C)c1Nc1nn(C)c2nc(Nc3ccc4CNCc4c3)ncc12 HPGKDPKCOGXQNZ-UHFFFAOYSA-N 0.000 description 1
- FXLWVUYNYMFVRT-UHFFFAOYSA-N 6-chloro-1-methyl-N-(2-methylphenyl)pyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1)C)C FXLWVUYNYMFVRT-UHFFFAOYSA-N 0.000 description 1
- KCNSXQLKJXRGMC-UHFFFAOYSA-N 6-chloro-N-(2,4-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1)C)C)C KCNSXQLKJXRGMC-UHFFFAOYSA-N 0.000 description 1
- ACGDUFAUABFHAZ-UHFFFAOYSA-N 6-chloro-N-(2,5-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC(=C1)C)C)C ACGDUFAUABFHAZ-UHFFFAOYSA-N 0.000 description 1
- KHXOYPYIIRDIEI-UHFFFAOYSA-N 6-chloro-N-(2,6-diethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1CC)CC)C KHXOYPYIIRDIEI-UHFFFAOYSA-N 0.000 description 1
- RVSZYJMOKFELJF-UHFFFAOYSA-N 6-chloro-N-(2,6-difluorophenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1F)F)C RVSZYJMOKFELJF-UHFFFAOYSA-N 0.000 description 1
- DRYSYFNANWLCIX-UHFFFAOYSA-N 6-chloro-N-(2,6-dimethoxyphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1OC)OC)C DRYSYFNANWLCIX-UHFFFAOYSA-N 0.000 description 1
- RQGHXZRXGUOLNY-UHFFFAOYSA-N 6-chloro-N-(2,6-dimethyl-4-phenoxyphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)OC1=CC=CC=C1)C)C RQGHXZRXGUOLNY-UHFFFAOYSA-N 0.000 description 1
- RYYLSQXWLSXORR-UHFFFAOYSA-N 6-chloro-N-(2-chloro-6-methylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C)Cl)C RYYLSQXWLSXORR-UHFFFAOYSA-N 0.000 description 1
- UZUVXTWZARMQEN-UHFFFAOYSA-N 6-chloro-N-(3,5-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=CC(=CC(=C1)C)C)C UZUVXTWZARMQEN-UHFFFAOYSA-N 0.000 description 1
- HAXTZKFUBXOBJL-UHFFFAOYSA-N 6-chloro-N-(4-fluoro-2,6-dimethylphenyl)-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=C(C=C1C)F)C)C HAXTZKFUBXOBJL-UHFFFAOYSA-N 0.000 description 1
- MGZAKSHPRVJLMK-UHFFFAOYSA-N 6-chloro-N-[2,6-di(propan-2-yl)phenyl]-1-methylpyrazolo[3,4-d]pyrimidin-3-amine Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC1=C(C=CC=C1C(C)C)C(C)C)C MGZAKSHPRVJLMK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 0 C*1(CC1)C(N(CC1)Cc2c1ccc(Nc1ncc(c(Nc3c(C)ccc(NC(Nc4cc(C(F)(F)F)ccc4)=O)c3)n[n]3)c3n1)c2)=O Chemical compound C*1(CC1)C(N(CC1)Cc2c1ccc(Nc1ncc(c(Nc3c(C)ccc(NC(Nc4cc(C(F)(F)F)ccc4)=O)c3)n[n]3)c3n1)c2)=O 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- CHLVCLJWWORYDT-VQHVLOKHSA-N Cc(c(Nc1n[n](C)c2nc(Cl)ncc12)c1)ccc1NC(/C=C/c1cccc(C(F)(F)F)c1)=O Chemical compound Cc(c(Nc1n[n](C)c2nc(Cl)ncc12)c1)ccc1NC(/C=C/c1cccc(C(F)(F)F)c1)=O CHLVCLJWWORYDT-VQHVLOKHSA-N 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 239000001512 FEMA 4601 Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- HYTGXZNJWSPHGH-UHFFFAOYSA-N N-(2,4-dimethyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=CC(=C1[N+](=O)[O-])C)NC(C1=CC(=CC=C1)C(F)(F)F)=O HYTGXZNJWSPHGH-UHFFFAOYSA-N 0.000 description 1
- ORKSNKJCMDROHG-UHFFFAOYSA-N N-(4-ethoxy-4-nitrocyclohexa-1,5-dien-1-yl)acetamide Chemical compound C(C)(=O)NC1=CCC(C=C1)(OCC)[N+](=O)[O-] ORKSNKJCMDROHG-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- CMBYJKCVZPGRCF-UHFFFAOYSA-N N-[3-[(6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-3-yl)amino]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound ClC1=NC=C2C(=N1)N(N=C2NC=1C=C(C=CC=1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C CMBYJKCVZPGRCF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000011158 Prunus mume Nutrition 0.000 description 1
- 244000018795 Prunus mume Species 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- HELXLJCILKEWJH-SEAGSNCFSA-N Rebaudioside A Natural products O=C(O[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@]1(C)[C@@H]2[C@](C)([C@H]3[C@@]4(CC(=C)[C@@](O[C@H]5[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@H](O)[C@@H](CO)O5)(C4)CC3)CC2)CCC1 HELXLJCILKEWJH-SEAGSNCFSA-N 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 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 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003471 Vitamin B2 Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-L acetylenedicarboxylate(2-) Chemical compound [O-]C(=O)C#CC([O-])=O YTIVTFGABIZHHX-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose 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-QUYVBRFLSA-N 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229940037769 calcium carbonate 100 mg Drugs 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940069647 citric acid 1000 mg Drugs 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- JZRHODNPRNTXKO-UHFFFAOYSA-N cyclohexylhydrazine;hydrochloride Chemical compound Cl.NNC1CCCCC1 JZRHODNPRNTXKO-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- GONHTJWVIZVBOU-UHFFFAOYSA-N cyclopentylhydrazine;hydron;chloride Chemical compound Cl.NNC1CCCC1 GONHTJWVIZVBOU-UHFFFAOYSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- USLKCMBGQFYUFI-UHFFFAOYSA-N dichloromethane;tribromoborane Chemical compound ClCCl.BrB(Br)Br USLKCMBGQFYUFI-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- HELXLJCILKEWJH-UHFFFAOYSA-N entered according to Sigma 01432 Natural products C1CC2C3(C)CCCC(C)(C(=O)OC4C(C(O)C(O)C(CO)O4)O)C3CCC2(C2)CC(=C)C21OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O HELXLJCILKEWJH-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000000442 hair follicle cell Anatomy 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- VIPHVHVAGBKHGR-UHFFFAOYSA-N hydron;pyridine-2-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CC=N1 VIPHVHVAGBKHGR-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical group C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 108091005434 innate immune receptors Proteins 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 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
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 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
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- UFOJNUSJWKEEEQ-UHFFFAOYSA-N n-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide Chemical compound C1=C(N)C(C)=CC=C1NC(=O)C1=CC=CC(C(F)(F)F)=C1 UFOJNUSJWKEEEQ-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
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000013642 negative control Substances 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
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 235000015074 other food component Nutrition 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 229960003418 phenoxybenzamine Drugs 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- KJAQRHMKLVGSCG-UHFFFAOYSA-N propan-2-ylhydrazine Chemical compound CC(C)NN KJAQRHMKLVGSCG-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000019203 rebaudioside A Nutrition 0.000 description 1
- 210000005132 reproductive cell Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- YRLQFRXDWBFGMK-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C=C1 YRLQFRXDWBFGMK-UHFFFAOYSA-N 0.000 description 1
- PKYRLRVLXYAKPM-UHFFFAOYSA-N tert-butyl 4-(4-nitrophenyl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C=CC(=CC=2)[N+]([O-])=O)=C1 PKYRLRVLXYAKPM-UHFFFAOYSA-N 0.000 description 1
- RZHCQZWEGZHOHP-UHFFFAOYSA-N tert-butyl n-(1,4-dioxaspiro[4.5]decan-8-ylamino)carbamate Chemical compound C1CC(NNC(=O)OC(C)(C)C)CCC21OCCO2 RZHCQZWEGZHOHP-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940033203 vitamin b6 0.5 mg Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000007279 water homeostasis Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
- A23L33/155—Vitamins A or D
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
- A23L2/56—Flavouring or bittering agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
- A23L2/68—Acidifying substances
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to a pyrazolopyrimidine derivative, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient for the prevention or treatment of cancer, autoimmune disease and brain disease.
- Cancer is defined by the abnormal state of cells, wherein cell death is not controlled normally because of various changes in gene expression, and abnormal cell growth is induced. Cancer cells penetrate into neighboring tissues and destroy thereof, and migrate to other regions, which can result in human death.
- the cause of cancer that is, the mechanism by which normal cells are transfected into cancer cells, has not been clearly identified. It is known that the causes of cancer include environmental factors, external factors such as chemicals, radiation, and viruses, and internal factors such as genetic factors and immunological factors, and those factors interact complicate to cause cancer.
- Cancer is largely divided into blood cancer characterized by abnormal blood cell number and solid cancer in the form of cell mass that has a certain degree of hardness and shape in the body. Cancer can be developed in blood and almost all parts of the body, which can be exemplified by lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer and skin cancer.
- Major treatment methods for cancer are surgery, radio-therapy, and chemo-therapy using a chemotherapeutic agent inhibiting cell proliferation.
- a chemotherapeutic agent is not a target-specific agent that directly acts on the target of each cancer. Therefore, repeated chemotherapy treatments result in side effects due to cytotoxicity and resistance to the drugs, indicating that, despite the initial successful response to the anticancer drug, if the cancer treatment duration is prolonged or the cancer recurs, the treatment will fail because of such side effects and drug resistance.
- molecular biological factors are widely used to predict the prognosis of cancer or to determine the treatment method, either chemo-therapy or radio-therapy.
- the conventional cancer drugs have been constructed by targeting the rapid cell division characteristics of tumor cells, indicating they are targeting not only tumor cells but also normal cells showing relatively fast cell division (for example, hair follicle cells, gastrointestinal cells, bone marrow cells, reproductive cells), which causes serious side effects. Therefore, it is required to develop a novel anticancer agent that is specifically expressed only in tumor cells and not expressed in normal cells or has no effect on normal cells.
- Bruton's tyrosine kinase is a nonreceptor tyrosine kinase located on chromosome Xq22, which belongs to Tec family kinase.
- Bruton's tyrosine kinase plays an important role in the downstream signaling of growth factors, B-cell antigens, chemokine receptors and innate immune receptors. That is, BTK is an important protein that plays an important role in various cell activities such as cell growth, survival, differentiation, pathogenesis, angiogenesis, signaling molecule production, and antigen presentation, and thus it is known to play a crucial role in signal transduction of B-cell immunity, inflammation, and anticancer.
- BTK Bruton's tyrosine kinase
- BTK Bruton's tyrosine kinase
- the present inventors have tried to overcome the problems of resistance and side effects according to the co-treatment with immuno-therapy of the conventional BTK inhibitors and to develop a compound with significantly excellent anticancer effect by reversibly inhibiting BTK.
- the present inventors confirmed that the compound of the present invention exhibited significantly excellent Bruton's tyrosine kinase inhibitory effect in animal tests, so that the compound could be used effectively in the treatment of cancer, autoimmune disease and Parkinson's disease, leading to the completion of the present invention.
- It is also an object of the present invention to provide a pharmaceutical composition comprising the pyrazolopyrimidine compound above as an active ingredient for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
- the present invention provides a compound represented by formula 1 below or a pharmaceutically acceptable salt of the same:
- R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in this specification).
- the present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1), as shown in reaction formula 1 below:
- R 1 , R 2 , R 3 , R 4 , R 5 , and X are as defined in this specification).
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
- the present invention also provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of cancer, autoimmune disease or Parkinson's disease.
- the present invention also provides a method for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease comprising the step of administering the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient to a subject in need.
- the present invention provides a use of the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
- the present invention also provides a method of treating a subject having a cancer comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the present invention also provides a method of treating a subject having an autoimmune disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the present invention also provides a method of treating a subject having a Parkinson's disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
- the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
- the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use as a medicament.
- the present invention also provides a medicament comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the pyrazolopyrimidine derivative of the present invention demonstrates an excellent Bruton's tyrosine kinase (BTK) inhibitory activity, so that a pharmaceutical composition comprising the compound of the invention as an active ingredient can be effectively used for the prevention or treatment of cancer, autoimmune disease and Parkinson's disease.
- BTK Bruton's tyrosine kinase
- the pyrazolopyrimidine derivative of the present invention can be used for immunotherapy because it does not inhibit ITK (Interlukin-2 receptor inducible T-cell kinase) and can be used as an autoimmune disease therapeutic agent for long-term administration because it is a reversible inhibitor.
- ITK Interlukin-2 receptor inducible T-cell kinase
- the derivative of the invention also shows an excellent pharmaceutical effect on Abl and Abl mutants along with excellent BBB permeability, so that it can be effectively used for the treatment of Parkinson's disease.
- Figure 1 is a schematic diagram illustrating the enzyme liked immuosrobent assay performed for measuring the concentration of TNFa.
- Heterocyclic ring means a saturated or partially unsaturated heterocyclic ring of 3 to 8 ring atoms (refers to a carbocyclic radical having one or more double or triple bonds in the ring without directionality) which contains at least one of hetero atoms selected from the group consisting of N, O and S and the remaining ring atoms are carbon. In a preferred embodiment of the present invention, it refers to monoheterocyclic consisting of one ring, wherein the hetero atom means a nitrogen atom or an oxygen atom.
- it can be pyrrolidine, dihydrofuran, tetrahydrothiophene, tetrahydropyrane, dihydropyrane, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, thioxane, piperazine, azetidine, oxetane, thietane, oxepan, oxazepine, diazepine, thiazepine, 2-pyrroline, or 3-pyrroline.
- “Cycloalkane” is a saturated or partly unsaturated (i.e., nonaromatic) group containing all carbon ring atoms.
- it can be cyclohexene, cyclohexane, cyclopentene, cyclopentane, cyclobutene, cyclobutane, or cyclopropane.
- Alkyl is a branched or straight-chain saturated aliphatic hydrocarbon group.
- the alkyl contains 1 ⁇ 5 carbon atoms or 1 ⁇ 3 carbon atoms.
- it can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, or neopentyl.
- Alkenyl is a branched or straight-chain aliphatic hydrocarbon group having at least one carbon-carbon double bond that can occur along the chain at a stable point.
- the alkenyl contains 2 ⁇ 5 carbon atoms.
- it can be ethenyl or propenyl.
- Alkynyl is a branched or straight-chain aliphatic hydrocarbon group having at least one carbon-carbon triple bond that can occur along the chain at any stable point.
- the alkynyl contains 2 ⁇ 5 carbon atoms.
- it can be ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, or 4-pentynyl.
- Dialkyl indicates an alkyl substituted group as defined above wherein two same or different alkyls are substituted.
- Alkoxy is an alkyl group as defined above covalently bonded through an oxygen bridge (-O-).
- Hydroalkyl is an alkyl group as described above substituted with one or more hydroxy substituents.
- Haloalkyl indicates a branched or straight alkyl group substituted with one or more halogen atoms and up to a maximum number of halogen atoms. For example, it can be trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, or penta-fluoroethyl.
- Cycloalkyl is a saturated or partly unsaturated (i.e., nonaromatic) group containing all carbon ring atoms.
- it can be cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, or cyclopropyl.
- Alkyloxyalkyl is an alkyl group as defined above wherein additional alkyl is covalently bonded through an oxygen bridge (-O-).
- Aryl indicates an aromatic group containing only carbon in the aromatic ring. In a preferred embodiment of the present invention, it may be phenyl or naphthalenyl.
- Heteroaryl indicates a stable 5 ⁇ 12 membered monocyclic aromatic ring, bicyclic or tricyclic system containing one or more hetero atoms selected from the group consisting of N, O and S and the remaining ring atoms are carbon. In a preferred embodiment of the present invention, the only hetero atom is nitrogen.
- the monocyclic heteroaryl group typically has 5 ⁇ 7 ring atoms.
- the bicyclic heteroaryl group is a 9 or 10 membered heteroaryl group wherein a 5 ⁇ 7 membered aromatic ring is fused with the second aromatic or non-aromatic ring and 9 ⁇ 10 ring atoms are contained.
- the heteroaryl group is exemplified by pyridinyl (including 2-hydroxypyridinyl), imidazolyl, imidazolopyridinyl, pyrimidinyl (including 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazoly
- Halo or "halogen” independently represents any fluoro, chloro, bromo, and iodo.
- the present invention provides a compound represented by formula 1 below or a pharmaceutically acceptable salt of the same:
- A is 3 ⁇ 8 membered heterocyclic ring containing one or more hetero atoms selected from the group consisting of N, O and S or C 3-10 cycloalkane;
- R 3 , R 4 , and R 5 are independently hydrogen, straight or branched C 1-5 alkyl or C 3-8 cycloalkyl. At this time, the alkyl or cycloalkyl can be substituted with hydroxy; and
- A is 3 ⁇ 6 membered heterocyclic ring containing one or more hetero atoms selected from the group consisting of N, O and S or C 5-7 cycloalkane;
- R 3 , R 4 , and R 5 are independently hydrogen, straight or branched C 1-3 alkyl or C 3-6 cycloalkyl. At this time, the alkyl or cycloalkyl can be substituted with hydroxy; and
- R 10 is straight or branched C 1-3 alkyl or C 1-3 alkyloxy C 1-3 alkyl; C 5-10 aryl; or 6 ⁇ 10 membered heteroaryl containing one or more nitrogen atoms; and the aryl or heteroaryl can be substituted with one or more substituents selected from the group consisting of straight or branched C 1-3 alkyl, C 1-3 alkoxy and C 1-3 haloalkyl.
- A is piperidine, tetrahydropyrane, pyrrolidine, or cyclohexane
- R 2 is hydrogen or methoxy
- R 3 is hydrogen
- R 4 is hydrogen, methyl, isopropyl, cyclopentyl, cyclohexyl, or (4-hydroxy)cyclohexyl;
- R 5 is hydrogen
- R 6 is one or more substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, chloro, fluoro, methoxyethoxy, phenoxy, , , , and .
- the compound represented by formula 1 above is any one selected from the group consisting of the following compounds:
- the compound represented by formula 1 of the present invention can be used as a form of a pharmaceutically acceptable salt, in which the salt is preferably acid addition salt formed by pharmaceutically acceptable free acids.
- the acid addition salt herein can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic mono/dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate, alkandioate, aromatic acids, and aliphatic/aromatic sulfonic acids; or organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid.
- inorganic acids such as hydrochloric acid, nitric
- the pharmaceutically non-toxic salts are exemplified by sulfate, pyrosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, maliate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, tolu
- the acid addition salt in this invention can be prepared by the conventional method known to those in the art.
- the derivative represented by formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylenechloride, or acetonitrile, to which organic acid or inorganic acid is added to induce precipitation.
- the precipitate is filtered and dried to give the salt.
- the solvent and the excessive acid are distillated under reduced pressure, and dried to give the salt.
- the precipitate is crystallized in an organic solvent to give the same.
- a pharmaceutically acceptable metal salt can be prepared by using a base.
- Alkali metal or alkali earth metal salt is obtained by the following processes: dissolving the compound in excessive alkali metal hydroxide or alkali earth metal hydroxide solution; filtering non-soluble compound salt; evaporating the remaining solution and drying thereof.
- the metal salt is preferably prepared in the pharmaceutically suitable form of sodium, potassium, or calcium salt.
- the corresponding silver salt is prepared by the reaction of alkali metal or alkali earth metal salt with proper silver salt (ex; silver nitrate).
- the present invention includes not only the compound represented by formula 1 but also a pharmaceutically acceptable salt thereof, and a solvate, an optical isomer, or a hydrate possibly produced from the same.
- the present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1), as shown in reaction formula 1 below:
- R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in formula 1, and
- X is halogen
- step 1 is to prepare the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3.
- step 1 is a step of condensing an amine group (-NHR 5 ) of the compound represented by formula 2 and a halogen group (X) of the compound represented by formula 3 in the presence of an acid.
- the acid is not particularly limited as long as it is an acid generally used in the field, but trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TSA), hydrochloric acid (HCl) and formic acid can be used.
- TFA trifluoroacetic acid
- p-TSA p-toluenesulfonic acid
- HCl hydrochloric acid
- formic acid formic acid can be used.
- the reaction temperature is not limited but can be 10 ⁇ 150°C, preferably 30 ⁇ 120°C, and more preferably 50 ⁇ 100°C. Most preferably, the reaction temperature can be the boiling point of the organic solvent used in the reaction.
- reaction solvent is not particularly limited as long as it is an organic solvent generally used in the field, but isopropanol, butanol, and 1,4-dioxane can be used.
- step 1 preparing the compound represented by formula 3-3 by reacting the compound represented by formula 3-1 with the compound represented by formula 3-2 via amidation (step 1);
- step 2 preparing the compound represented by formula 3-5 by reacting the compound represented by formula 3-3 prepared in step 1 with the compound represented by formula 3-4 with the addition of hydrazine (step 2);
- step 3 cyclizing the compound represented by formula 3-5 prepared in step 2 (step 3).
- R 3 , R 4, and R 5 are as defined in formula 1, and X is halogen.
- reaction conditions for step 1 ⁇ step 3 shown in reaction formula 2 above are not particularly limited as long as they are generally used in the art, so that the detailed description is omitted herein.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.
- the compound is characterized by being effective in preventing or treating cancer by inhibiting Bruton's tyrosine kinase (BTK).
- BTK Bruton's tyrosine kinase
- the cancer can be solid cancer or blood cancer.
- the solid tumor can be selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, uveal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small bowel cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervix cancer, endometrial cancer
- composition comprising the compound represented by formula 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer can be administered independently or co-administered with other anticancer agents in use.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of autoimmune disease.
- the compound is characterized by being effective in preventing or treating autoimmune disease by inhibiting Bruton's tyrosine kinase (BTK).
- the autoimmune disease can be selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guilin Barre syndrome, acute sporadic encephalomyelitis, Addison's disease, ocular hepatocellular seizure-epileptic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive dysfunction, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary dysplasia cirrhosis, Takay
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of Parkinson's disease.
- the compound represented by formula 1 or the pharmaceutically acceptable salt thereof included in the pharmaceutical composition of the present invention can be administered orally or parenterally and be used in general forms of pharmaceutical formulation. That is, the composition of the present invention can be prepared for oral or parenteral administration by mixing with generally used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants.
- the formulations for oral administration are exemplified by tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and troches, etc.
- These formulations can include diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine) and lubricants (for example, silica, talc, stearate and its magnesium or calcium salt, and/or polyethylene glycol) in addition to the active ingredient.
- Tablets can include binding agents such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrolidone, and if necessary disintegrating agents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents, coloring agents, flavours, and sweeteners can be additionally included thereto.
- binding agents such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrolidone
- disintegrating agents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents, coloring agents, flavours, and sweeteners can be additionally included thereto.
- the pharmaceutical composition comprising the compound represented by formula 1 as an active ingredient can be administered by parenterally and the parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
- the compound represented by formula 1 or the pharmaceutically acceptable salt thereof is mixed with a stabilizer or a buffering agent in water to produce a solution or suspension, which is then formulated as ampoules or vials.
- the composition herein can be sterilized and additionally contains preservatives, stabilizers, wettable powders or emulsifiers, salts and/or buffers for the regulation of osmotic pressure, and other therapeutically useful materials, and the composition can be formulated by the conventional mixing, granulating or coating method.
- the effective dosage of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof of the present invention can be determined according to age, weight, gender, administration method, health condition, and severity of disease.
- the dosage is generally 0.1 ⁇ 1000 mg/day, and preferably 1 ⁇ 500 mg/day based on an adult patient weighing 70 kg, which can be administered once or several times a day at intervals of a certain time depending on the judgment of a doctor or a pharmacist.
- composition comprising the compound represented by formula 1, the optical isomer, or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer can be administered as an individual therapeutic agent or in combination with other anticancer agents in use.
- the present invention also provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of cancer.
- the present invention also provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of autoimmune disease.
- the present invention provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of Parkinson's disease.
- the compound represented by formula 1 of the present invention can be used as a food additive.
- the compound represented by formula 1 of the present invention can be added as it is or as mixed with other food components according to the conventional method.
- the mixing ratio of active ingredients can be regulated according to the purpose of use (prevention or improvement).
- the compound of the present invention is preferably added to food or beverages by 0.1 ⁇ 90 weight part for the total weight of the food or beverages.
- the content can be lower than the above but higher content can be accepted as well since the compound of the present invention has been proved to be very safe.
- the health beverage composition of the present invention can additionally include various flavors or natural carbohydrates, etc, like other beverages.
- the natural carbohydrates above can be one of monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xilytole, sorbitol and erythritol.
- natural sweetening agents thaumatin, stevia extract, for example rebaudioside A, glycyrrhizin, etc.
- synthetic sweetening agents sacharin, aspartame, etc.
- the content of the natural carbohydrate is preferably 1 ⁇ 20 g and more preferably 5 ⁇ 12 g in 100 g of the composition of the invention.
- the compound represented by formula 1 of the present invention can include in variety of nutrients, vitamins, minerals (electrolytes), flavors including natural flavors and synthetic flavors, coloring agents and extenders (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acid, protective colloidal viscosifiers, pH regulators, stabilizers, antiseptics, glycerin, alcohols, carbonators which used to be added to soda, etc.
- the compound represented by formula 1 of the present invention can also include natural fruit juice, fruit beverages and fruit flesh addable to vegetable beverages.
- the present invention also provides a method for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease comprising the step of administering the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient to a subject in need.
- the present invention provides a use of the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
- the present invention also provides a method of treating a subject having a cancer comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the present invention also provides a method of treating a subject having an autoimmune disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the present invention also provides a method of treating a subject having a Parkinson's disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
- the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
- the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
- the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use as a medicament.
- the present invention also provides a medicament comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
- novel pyrazolopyrimidine compound of the present invention demonstrates an excellent BTK inhibitory activity at a low concentration, and therefore it can be used as a pharmaceutical composition for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease, which is supported by the results of the following experiments.
- Trifluoro acetic anhydride (0.43 mL, 2.99 mmol) was added to 2-(4-bromophenyl)ethane-1-amine (500 mg, 2.50 mmol) solution in DCM (25 mL), to which TEA (0.87 mL, 6.25 mmol) was added.
- the reaction mixture was stirred at room temperature for 1 hour.
- water 50 mL was added to the reaction mixture, followed by extraction with DCM (2 X 50 mL).
- the combined organic layer was washed with saturated brine solution, which was dried over Na 2 SO 4 .
- the solvent was eliminated in vacuum.
- the crude mixture was purified by re-crystallization. As a result, N-(4-bromophenetyl)-2,2,2-trifluoroacetamide (700 mg, 2.36 mmol, 94%) was obtained as a white solid.
- Step 2 Preparation of 1-(7-bromo-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- step 1 Compound of step 1 (250 mg, 0.844 mmol) was dissolved in HOAc (1.41 mL) and sulfuric acid (0.94 mL), to which paraformaldehyde (40 mg, 1.35 mmol) was added at room temperature, followed by stirring for 12 hours.
- the reaction mixture was poured carefully into approximately 10 mL of ice.
- the generated white sludge suspension was extracted with EtOAc.
- the organic material was washed with saturated aqueous NaHCO 3 and brine, followed by drying over MgSO 4 .
- the crude mixture was purified by column chromatography using EtOAc/Hx (1:4) as an eluent.
- Step 3 Preparation of 1-(7-bromo-6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- Step 4 Preparation of 1-(6-amino-3,4-dihydroisoquinoline-2(1 H )-yl)-2,2,2-trifluoroethane-1-one
- Trifluoro acetic anhydride (6.22 g, 29.61 mmol) was added to 2-(4-nitrophenyl)ethane-1-amine (5.0 g, 24.67 mmol) solution in DCM (100 mL), to which TEA (8.6 mL, 61.67 mmol) was added.
- the reaction mixture was stirred at room temperature for 2 hours.
- water 50 mL was added to the reaction mixture, followed by extraction with DCM (2 X 50 mL).
- the combined organic layer was washed with saturated brine solution, which was dried over Na 2 SO 4 .
- the solvent was eliminated in vacuum.
- the crude mixture was purified by re-crystallization. As a result, 2,2,2-trifluoro-N-(4-nitrophenetyl)acetamide (5.8 g, 22.1 mmol, 90%) was obtained as a grey-white solid.
- step 1 Compound of step 1 (750 mg, 2.86 mmol) was dissolved in HOAc (4 mL), to which sulfuric acid (7.5 mL) and paraformaldehyde (137 mg, 4.57 mmol) were added at room temperature, followed by stirring at 50°C for 12 hours.
- the reaction mixture was poured carefully into approximately 100 mL of ice.
- the generated white sludge suspension was extracted with EtOAc.
- the organic material was washed with saturated aqueous NaHCO 3 and brine, followed by drying over MgSO 4 .
- the crude mixture was purified by column chromatography using hexane/EA (1:4) as an eluent.
- Step 3 Preparation of 1-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- step 1 Compound of step 1 (4.0 g, 12.3 mmol) was dissolved in 30 mL of methanol, to which 30 mL of sodium hydroxide solution (2.7 g, 67.6 mmol) was added at room temperature, followed by stirring at room temperature for 5 hours. Most of methane was concentrated under reduced pressure, and pH of the residue was adjusted to 2 with conc. HCl. The solid was precipitated and filtered. The filtered cake was washed with water and dried. As a result, 2-(carboxymethyl)-5-nitrobenzoic acid (2.2 g, 9.77 mmol, 79%) was obtained as a cream type solid.
- BH 3 THF (1.0 M) (21 mL, 21.03 mmol) was added to cold compound of step 1 (1.0 g, 5.25 mmol) THF (25 mL) solution at 0°C.
- the reaction mixture was stirred at 70°C for 2 hours.
- the reaction was terminated with methanol, followed by concentration and drying.
- 1.5 N HCl (15.00 mL) was added to the residue, followed by extraction with EtOAc.
- the aqueous layer was basified with NaOH solution and extracted with EtOAc (2 X 50 mL).
- the combined organic layer was washed with sodium sulfate and the remaining mixture was subjected to the following steps without any purification process.
- Step 3 Preparation of 1-(4,4-dimethyl-7-nitro-3,4-dihydroisoquinoline-2(1 H )-yl)-2,2,2-trifluoroethane-1-one
- Step 4 Preparation of 1-(7-amino-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- Step 4 Preparation of 2,2,2-trifluoro-1-(1-isopropyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
- Step 5 Preparation of 1-(7-amino-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- Step 3 Preparation of 2,2,2-trifluoro-1-(1,3,3-trimethyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
- Step 4 Preparation of 1-(7-amino-1,3,3-trimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- Trifluoroacetic anhydride (1.64 mL, 11.7 mmol) was added dropwise to cold isoindolin (400 mg, 3.35 mmol) acetonitrile (15 mL) solution at -10°C.
- Potassium nitrate (366 mg, 3.62 mmol) was added to the stirred mixture at once. The mixture was stirred at -10°C for 1 hour. Saturated sodium bicarbonate aqueous solution (10 mL) was slowly added to the mixture. Active gas generation was observed. The mixture was stirred for 1 hour and then the temperature of the mixture was raised to room temperature. The mixture was basified with saturated sodium carbonate (10 mL). The sticky turbid solution was filtered.
- a target compound was prepared by the same manner as described in step 4 of Preparative Example A-7 except that 2,2,2-trifluoro-1-(5-nitroisoindolin-2-yl)ethane-1-one prepared in step 1 was used instead of 2,2,2-TRIFLUORO-1-(1,3,3-TRIMETHYL-7-NITRO-3,4-DIHYDROISOQUINOLINE-2(1H)-YL)ETHANE-1-ONE.
- Step 5 Preparation of 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
- Step 6 Preparation of 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
- Step 7 Preparation of 2,2,2-trifluoro-1-(6-hydroxy-1,1-dimethyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
- Step 8 Preparation of 1,1-dimethyl-7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl trifluoromethanesulfonate
- Step 9 Preparation of 1-(7-amino-1,1-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- N -(4-nitrophenyl)acrylamide 200 mg, 1.04 mmol was suspended in ethanol/water (5:1) mixture, to which Fe powder (116 mg, 2.08 mmol) and ammonium chloride solution (1 mL) were added. The mixture was heated to 80°C for 4 hours. The reaction mixture was cooled at room temperature and filtered with a celite pad. The celite above was washed with ethanol (10 mL) and ethyl acetate (50 mL). The solution above was concentrated under vacuum. The reaction residue was fractionated with DCM (50 mL) and water (20 mL). The combined organic layer was concentrated under reduced pressure. The obtained crude mixture was purified by column chromatography (EtOAc/Hexane (1:5)). As a result, N -(4-aminophenyl)acrylamide (100 mg, 0.616 mmol, 60%) was obtained as a yellow solid.
- Fuming nitric acid (128 mg, 2.04 mmol) was added dropwise to -5°C conc. sulfuric acid (2.0 mL) containing 3,4-dihydroisoquinolin-1(2H)-one (400 mg, 2.31 mmol) at 0°C. The temperature of the mixture was raised to room temperature for 2 hours. The reaction mixture was placed in ice-water (10 mL) and basified with potassium hydroxide pellet (pH 9). The mixture was extracted with dichloromethane, followed by drying. The solvent was eliminated under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM (1:9)). As a result, 7-nitro-3,4-dihydroisoquinoline-1(2H)-one (300 mg, 1.56 mmol, 76%) was obtained as brown oil.
- a target compound was prepared by the same manner as described in step 4 of Preparative Example A-7 except that 7-nitro-3,4-dihydroisoquinoline-1(2H)-one prepared in step 1 was used instead of 2,2,2-TRIFLUORO-1-(1,3,3-TRIMETHYL-7-NITRO-3,4-DIHYDROISOQUINOLINE-2(1H)-YL)ETHANE-1-ONE.
- 2,6-Dimethylaniline (5.81 g, 48 mmol) was added to 2,4-dichloropyrimidine-5-carbonyl chloride (10.2 g, 48 mmol) in EtOAc (400 mL) at room temperature, to which amberlyst 21 resin (2.0 g) was added. The mixture was stirred at room temperature for 12 hours, followed by filtering. The filtrate was washed serially with water, 1.5 N HCl (15 mL), NaOH, and brine in that order. The combined organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was recrystallized by using DCM.
- Methyl hydrazine (205 mg, 4.45 mmol) was added to 2,4-DICHLORO-N-(2,6-DIMETHYLPHENYL)PYRIMIDINE-5-CARBOXAMIDE(1.2 g, 4.05 mmol) in THF (30 mL) at room temperature, to which Et 3 N (1.42 mL, 10.1 mmol) was added. The mixture was stirred at room temperature for 24 hours, which was concentrated to eliminate THF. The reaction mixture was washed with water, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
- PCl 5 (681 mg, 3.27 mmol) was added to 2-CHLORO-N-(2,6-DIMETHYLPHENYL)-4-(1-METHYLHYDRAZINYL)PYRIMIDINE-5-CARBOXAMIDE(1.0 g, 3.27 mmol) in toluene (40 mL) at room temperature. The mixture was stirred at room temperature for 24 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
- 6-CHLORO-N-(2,6-DIMETHYLPHENYL)-1-METHYL-1H-PYRAZOLO[3,4-D]PYRIMIDINE-3-AMINE 800 mg, 2.78 mmol, 85 %) was obtained as a yellow solid.
- PCl 5 (150 mg, 0.720 mmol) was added to 2-chloro-4-(1-methylhydrazinyl)-N-phenylpyrimidine-5-carboxamide (200 mg, 0.720 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4). As a result, 6-chloro-1-methyl-N-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine (150 mg, 0.577 mmol, 80%) was obtained as a yellow solid.
- 2,6-Dichloroaniline (383 mg, 2.36 mmol) was added to 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.36 mmol) in EtOAc (40 mL) at room temperature, to which amberlyst 21 resin (100 mg) was added. The mixture was stirred for 12 hours, followed by filtering. The filtrate was washed with water, 1.5 N HCl (15 mL), NaOH, and brine in that order. The combined organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was recrystallized by using DCM. As a result, 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide (650 mg, 1.93 mmol, 81%) was obtained as a grey-white solid.
- PCl 5 120 mg, 0.577 mmol was added to 2-chloro-N-(2,6-dichlorophenyl)-4-(1-methylhydrazinyl)pyrimidine-5-carboxamide (200 mg, 0.577 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
- 6-chloro-N-(2,6-dichlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine 130 mg, 0.395 mmol, 68%) was obtained as a yellow solid.
- Step 1 Preparation of tert-butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyrimidine-4-yl)hydrazine-1-carboxylate
- tert-butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyrimidine-4-yl)hydrazine-1-carboxylate 560 mg, 1.429 mmol, 84%) was obtained as a white solid.
- PCl 5 (297 mg, 1.429 mmol) was added to tert-butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyrimidine-4-yl)hydrazine-1-carboxylate (560 mg, 1.429 mmol) in toluene (50 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4). As a result, 6-chloro-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine (65 mg, 0.237 mmol, 16%) was obtained as a yellow solid.
- Step 1 Preparation of 2-chloro-4-(1-cyclopentylhydrazinyl)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide
- Step 2 Preparation of 6-chloro-1-cyclopentyl-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine
- PCl 5 (104 mg, 0.500 mmol) was added to 2-chloro-4-(1-cyclopentylhydrazinyl)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide (180 mg, 0.500 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by column chromatography using EtOAc/Hx (1/4).
- 6-chloro-1-cyclopentyl-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine 120 mg, 0.351 mmol, 70% was obtained as a yellow solid.
- Step 1 Preparation of 2-chloro-4-(1-cyclohexylhydrazinyl)- N -(2,6-dimethylphenyl)pyrimidine-5-carboxamide
- Step 2 Preparation of 6-chloro-1-cyclohexyl- N -(2,6-dimethylphenyl)-1 H -pyrazolo[3,4-d]pyrimidine-3-amine
- PCl 5 (72 mg, 0.347 mmol) was added to 2-chloro-4-(1-cyclohexylhydrazinyl)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide (130 mg, 0.347 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 110°C for 3 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by column chromatography using EtOAc/Hx (1/4).
- 6-chloro-1-cyclohexyl-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine 90 mg, 0.253 mmol, 73%) was obtained as a yellow solid.
- Step 1 Preparation of 2-chloro- N -(2,6-dimethylphenyl)-4-(1-isopropylhydrazinyl)pyrimidine-5-carboxamide
- Et 3 N (0.18 mL, 1.26 mmol) was added to 2,4-dichloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide (150 mg, 0.506 mmol) in THF (10 mL), to which isopropyl hydrazine (41 mg, 0.577 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, which was concentrated to eliminate THF. The reaction mixture was washed with water, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
- Step 2 Preparation of 6-chloro- N -(2,6-dimethylphenyl)-1-isopropyl-1 H -pyrazolo[3,4-d]pyrimidine-3-amine
- PCl 5 (68.6 mg, 0.329 mmol) was added to 2-chloro-N-(2,6-dimethylphenyl)-4-(1-isopropylhydrazinyl)pyrimidine-5-carboxamide (110 mg, 0.329 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 110°C for 3 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
- 6-chloro-N-(2,6-dimethylphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine 75 mg, 0.237 mmol, 72%) was obtained as a yellow solid.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide prepared in step 4 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- Step 5 Preparation of N-(3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-2,4-dimethylphenyl)-3-(trifluoromethyl)benzamide
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that N-(3-amino-2,4-dimethylphenyl)-3-(trifluoromethyl)benzamide prepared in step 4 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- Step 2 Preparation of 6-chloro-N-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 4-(2-methoxyethoxy)-2,6-dimethylaniline prepared in step 1 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,6-dimethyl-4-phenoxybenzamine was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- T3P (2.30 mL, 10.2 mmol) and TEA (1.42 mL, 10.2 mmol) were added to DCM (20 mL) solution containing 3,5-dimethyl-4-nitrobenzoic acid (1.00 g, 5.12 mmol) and 2-aminopyridine (482 mg, 5.12 mmol) at room temperature, followed by stirring at room temperature overnight.
- the reaction was terminated with NaHCO 3 (aq), followed by extraction with DCM (2 X 25 mL).
- the combined organic layer was dried over Na 2 SO 4 and the solvent was eliminated under reduced pressure.
- the residue mixture was purified by silica gel column chromatography using EtOAc/Hex (3/7). As a result, the target compound (290 mg, 1.07 mmol, 21%) was obtained as a white solid.
- Step 3 Preparation of 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-3,5-dimethyl-N-(pyridine-2-yl)benzamide
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 4-amino-3,5-dimethyl-N-(pyridine-2-yl)benzamide prepared in step 2 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- Step 2 Preparation of 6-chloro-N-(4-methoxy-2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 4-methoxy-2,6-dimethylaniline prepared in step 1 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,4-diethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,4-diisopropylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- Step 1 Preparation of 2,4-dichloro- N -(3,5-dimethylphenyl)pyrimidine-5-carboxamide
- Step 2 Preparation of 2-chloro- N -(3,5-dimethylphenyl)-4-(1-methylhydrazinyl)pyrimidine-5-carboxamide
- Step 3 Preparation of 6-chloro- N -(2-chloro-3,5-dimethylphenyl)-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-amine
- PCl 5 (82 mg, 0.392 mmol) was added to 2-chloro-N-(3,5-dimethylphenyl)-4-(1-methylhydrazinyl)pyrimidine-5-carboxamide (120 mg, 0.392 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 110°C for 2 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4) as an eluent.
- 6-chloro-N-(2-chloro-3,5-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine 40 mg, 0.124 mmol, 32%) was obtained as a yellow solid.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,4-dimethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2-methylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 3,5-dimethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,6-difluoroaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,6-dimethoxyaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,5-dimethyl-4-fluoroaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,5-dimethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2-chloro-6-methylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 5-(2-methoxyethoxy)-2-methylaniline prepared in step 2 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2-methyl-5-nitroanilyl was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- Step 3 Preparation of N-(3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-4-methylphenyl)picolineamide
- Step 2 Preparation of 3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide
- a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide prepared in step 1 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
- Step 1 Preparation of N 1 -(6-chloro-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-yl)-6-methylbenzene-1,3-diamine
- N 1 -(6-chloro-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-yl)-6-methylbenzene-1,3-diamine 60 mg, 0.207 mmol, 66%) was obtained as a yellow solid.
- Step 2 Preparation of 1-(3-((6-chloro-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-yl)amino)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea
- N3-(2,6-dimethylphenyl)-1-methyl-N6-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (20 mg, 0.050 mmol, 50%) was obtained as a grey-white solid.
- Lithium hydroxide monohydrate (2.5 mg, 0.057 mmol) was added to THF (1.0 mL), MeOH (0.5 mL), and H 2 O (0.5 mL) containing the compound of Example 3 (1-(6-(3-(2,6-dimethylphenylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethaneone, 15 mg, 0.028 mmol) at room temperature, followed by stirring at room temperature for 1 hour. TLC analysis indicated the complete consumption of the starting material. The reaction mixture was concentrated to eliminate THF and methanol.
- a target compound was prepared by the same manner as described in Example 3 except that the compound prepared in Preparative Example A-2 was used instead of 1-(6-amino-7-methoxy-3,4 dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one in Example 3.
- a target compound was prepared by the same manner as described in Example 4 except that the compound of Example 6 was used instead of the compound of Example 3 in Example 4.
- a target compound was prepared by the same manner as described in Example 5 except that the compound of Example 7 was used instead of the compound of Example 4 in Example 5.
- a target compound was prepared by the same manner as described in Example 3 except that the compound prepared in Preparative Example A-3 was used instead of 1-(6-amino-7-methoxy-3,4 dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one and the compound prepared in Preparative Example B-2 was used instead of the compound prepared in Preparative Example B-1 in Example 3
- a target compound was prepared by the same manner as described in Example 4 except that the compound of Example 9 was used instead of the compound of Example 3 in Example 4.
- a target compound was prepared by the same manner as described in Example 9 except that the compound of Preparative Example B-3 was used instead of the compound of Preparative Example B-2 in Example 9.
- a target compound was prepared by the same manner as described in Example 10 except that the compound of Example 11 was used instead of the compound of Example 9 in Example 10.
- Example 14 Preparation of 1-(7-(3-(2,6-dimethylphenylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)prop-2-en -1-one
- Step 1 Preparation of 1-(6-((3-((2,6-dichlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- a target compound was prepared by the same manner as described in Example 6 except that the compound prepared in Preparative Example B-3 was used instead of the compound of Preparative Example B-1 in Example 6.
- Step 2 Preparation of N 3 -(2,6-dichlorophenyl)-1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine
- a target compound was prepared by the same manner as described in Example 7 except that the compound prepared in step 1 above was used instead of the compound of Example 6 in Example 7.
- a target compound was prepared by the same manner as described in Example 13 except that the compound of Example 15 was used instead of the compound of Example 12 in Example 13.
- Formalin (35%) (1.5 mg, 0.05 mmol) was added to MeOH (1.0 mL) and acetic acid (0.1 mL) containing the compound of Example 2 (1-(7-(3-(2,6-dimethylphenylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)prop-2-en -1-one, 10 mg, 0.025 mmol) at 0°C, followed by stirring at room temperature for 30 minutes. NaCNBH 3 (2.3 mg, 0.037 mmol) was added to the reaction mixture, which was stirred for 30 minutes.
- N3-(2,6-dimethylphenyl)-N6-(isochroman-7-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 50 mg, 0.125 mmol, 75%) was obtained as a grey-white solid.
- Step 1 Preparation of 1-(7-((3-((2,6-dimethylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
- a target compound was prepared by the same manner as described in Example 9 except that the compound of Preparative Example B-4 was used instead of the compound of Preparative Example B-2 in Example 9.
- Step 2 Preparation of N3-(2,6-dimethylphenyl)-N6-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine
- a target compound was prepared by the same manner as described in Example 10 except that the compound prepared in step 1 above was used instead of the compound of Example 9 in Example 10.
- Step 1 A target compound was prepared by the same manner as described in Example 3 except that 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 1-(6-amino-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one in Example 3.
- Step 2 A target compound was prepared by the same manner as described in Example 4 except that the compound prepared in step 1 above was used instead of the compound of Example 3 in Example 4.
- a target compound was prepared by the same manner as described in Example 22 except that cyclopropanecarboxylic acid was used instead of glycolic acid in Example 22.
- a target compound was prepared by the same manner as described in Example 22 except that iodoethanol was used instead of glycolic acid in Example 22.
- Example 25 Preparation of 1-cyclopentyl-N 3 -(2,6-dimethylphenyl)-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-5 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-6 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-7 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-8 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-9 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-10 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 22 except that N , N -dimethylglycine was used instead of glycolic acid in Example 22.
- a target compound was prepared by the same manner as described in Example 22 except that iodoethane was used instead of glycolic acid in Example 22.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-11 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-12 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-13 was used instead of the compound of Preparative Example B-4 in Example 19.
- Example 36 Preparation of N 3 -(2,6-diethylphenyl)-1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-14 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-15 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 10 except that the compound of Preparative Example B-16 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-17 was used instead of the compound of Preparative Example B-4 in Example 19.
- Example 40 Preparation of 1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-N 3 -o-tolyl-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-18 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-19 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-20 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-21 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-22 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-23 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 20 except that the compound of Preparative Example A-5 was used instead of 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in Example 20.
- a target compound was prepared by the same manner as described in Example 20 except that the compound of Preparative Example B-8 was used instead of the compound of Preparative Example B-1 in Example 20.
- Example 48 Preparation of N 3 -(2-chloro-6-methylphenyl)-1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-24 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 20 except that the compound of Preparative Example A-6 was used instead of 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in Example 20.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-25 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-26 was used instead of the compound of Preparative Example B-4 in Example 19.
- Example 52 Preparation of 4-methyl-3-(1-methyl-6-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)-1H-pyrazolo[3,4- d ]pyrimidine-3-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide
- a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-27 was used instead of the compound of Preparative Example B-4 in Example 19.
- a target compound was prepared by the same manner as described in Example 20 except that 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in Example 20.
- Example 54 Preparation of 4-(3-((2,6-dimethylphenyl)amino)-6-((1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)cyclohexane-1-ol
- Step 1 Preparation of tert-butyl2-(1,4-dioxaspiro[4.5]decane-8-yl)hydrazine-1-carboxylate
- Step 2 Preparation of tert -butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyridine-4-yl-2-(1,4-dioxaspiro[4.5]decane-8-yl)hydrazine-1-carboxylate
- Step 3 Preparation of 6-chloro-N-(2,6-dimethylphenyl)-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole[3,4-d]pyrimidine-3-amine
- PCl 5 (78 mg, 0.375 mmol) was added to toluene (20 mL) solution containing the compound prepared in step 2 above (200 mg, 0.375 mmol) at room temperature, followed by stirring at 110°C for 3 hours. The mixture was concentrated under reduced pressure to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The crude product was purified by column chromatography (EtOAc/Hx (1/4)). As a result, the target compound (80 mg, 0.193 mmol, 51%) was obtained as a yellow solid.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
La présente invention concerne un dérivé de pyrazolopyrimidine, son procédé de préparation et une composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau. Le dérivé de pyrazolopyrimidine de la présente invention présente une excellente activité d'inhibition de la tyrosine kinase de Bruton, de sorte qu'il peut être utilisé efficacement en tant que composition pharmaceutique pour la prévention ou le traitement du cancer, d'une maladie auto-immune et de la maladie de Parkinson.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/612,592 US11084824B2 (en) | 2017-05-12 | 2018-05-14 | Pyrazolopyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer, autoimmune disease and brain disease containing the same as an active ingredient |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20170059165 | 2017-05-12 | ||
KR10-2017-0059165 | 2017-05-12 | ||
KR1020180051686A KR102128018B1 (ko) | 2017-05-12 | 2018-05-04 | 피라졸로 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암, 자가면역질환 및 뇌질환의 예방 또는 치료용 약학적 조성물 |
KR10-2018-0051686 | 2018-05-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018208132A1 true WO2018208132A1 (fr) | 2018-11-15 |
Family
ID=64104794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2018/005478 WO2018208132A1 (fr) | 2017-05-12 | 2018-05-14 | Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2018208132A1 (fr) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019212256A1 (fr) * | 2018-05-02 | 2019-11-07 | 제이더블유중외제약 주식회사 | Nouveau dérivé hétérocyclique |
WO2020188015A1 (fr) | 2019-03-21 | 2020-09-24 | Onxeo | Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer |
WO2021089791A1 (fr) | 2019-11-08 | 2021-05-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase |
WO2021148581A1 (fr) | 2020-01-22 | 2021-07-29 | Onxeo | Nouvelle molécule dbait et son utilisation |
WO2022140246A1 (fr) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Procédés et composés destinés à l'autophagie ciblée |
WO2022197641A1 (fr) * | 2021-03-15 | 2022-09-22 | Rapt Therapeutics, Inc. | Dérivés de 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine servant de modulateurs et/ou d'inhibiteurs de kinase progénitrice hématopoïétique 1 (hpk1) pour traiter le cancer et d'autres maladies |
WO2022270994A1 (fr) * | 2021-06-25 | 2022-12-29 | 한국화학연구원 | Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation |
KR20230000983A (ko) * | 2021-06-25 | 2023-01-03 | 한국화학연구원 | 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007024680A1 (fr) * | 2005-08-22 | 2007-03-01 | Amgen Inc. | Composes de pyrazolopyridine et de pyrazolopyrimidine utilises comme modulateurs d'enzymes kinases |
WO2008112695A2 (fr) * | 2007-03-12 | 2008-09-18 | Irm Llc | Inhibiteurs de protéine kinase et procédés d'utilisation de ceux-ci |
WO2015048689A1 (fr) * | 2013-09-30 | 2015-04-02 | Pharmacyclics, Inc. | Inhibiteurs de la tyrosine kinase de bruton |
-
2018
- 2018-05-14 WO PCT/KR2018/005478 patent/WO2018208132A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007024680A1 (fr) * | 2005-08-22 | 2007-03-01 | Amgen Inc. | Composes de pyrazolopyridine et de pyrazolopyrimidine utilises comme modulateurs d'enzymes kinases |
WO2008112695A2 (fr) * | 2007-03-12 | 2008-09-18 | Irm Llc | Inhibiteurs de protéine kinase et procédés d'utilisation de ceux-ci |
WO2015048689A1 (fr) * | 2013-09-30 | 2015-04-02 | Pharmacyclics, Inc. | Inhibiteurs de la tyrosine kinase de bruton |
Non-Patent Citations (2)
Title |
---|
LEUNG, C. S. ET AL.: "Methyl Effects on Protein-Ligand Binding", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 9, 2012, pages 4489 - 4500, XP055556365 * |
WU, S. ET AL.: "Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 112, no. 50, 2015, pages 15480 - 15485, XP055556362 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019212256A1 (fr) * | 2018-05-02 | 2019-11-07 | 제이더블유중외제약 주식회사 | Nouveau dérivé hétérocyclique |
WO2020188015A1 (fr) | 2019-03-21 | 2020-09-24 | Onxeo | Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer |
WO2021089791A1 (fr) | 2019-11-08 | 2021-05-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase |
WO2021148581A1 (fr) | 2020-01-22 | 2021-07-29 | Onxeo | Nouvelle molécule dbait et son utilisation |
WO2022140246A1 (fr) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Procédés et composés destinés à l'autophagie ciblée |
WO2022197641A1 (fr) * | 2021-03-15 | 2022-09-22 | Rapt Therapeutics, Inc. | Dérivés de 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine servant de modulateurs et/ou d'inhibiteurs de kinase progénitrice hématopoïétique 1 (hpk1) pour traiter le cancer et d'autres maladies |
US11918582B2 (en) | 2021-03-15 | 2024-03-05 | Rapt Therapeutics, Inc. | Pyrazole pyrimidine compounds and uses thereof |
WO2022270994A1 (fr) * | 2021-06-25 | 2022-12-29 | 한국화학연구원 | Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation |
KR20230000983A (ko) * | 2021-06-25 | 2023-01-03 | 한국화학연구원 | 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도 |
KR102637915B1 (ko) | 2021-06-25 | 2024-02-19 | 한국화학연구원 | 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2018208132A1 (fr) | Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif | |
WO2021112538A1 (fr) | Agoniste du récepteur glp-1 | |
WO2020149723A1 (fr) | Dérivé de pyrrolopyrimidine et composition pharmaceutique pour la prévention ou le traitement d'une maladie liée à la protéine kinase le comprenant en tant que principe actif | |
WO2020096372A1 (fr) | Nouveau dérivé de pipéridine-2,6-dione et utilisation associée | |
WO2014061970A1 (fr) | Bloqueurs de canal sodique, leur procédé de préparation et leur utilisation | |
WO2015160192A1 (fr) | Composition pharmaceutique permettant de traiter et de prévenir la leucémie, contenant un dérivé de thiénopyrimidine ou un sel pharmaceutiquement acceptable de celui-ci | |
WO2020149715A1 (fr) | Dérivé de pyrrolopyridine et son utilisation dans la prévention et le traitement d'une maladie liée à la protéine kinase | |
WO2014109530A1 (fr) | Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer | |
WO2018021826A1 (fr) | Nouveau dérivé de pyrimidine-2,4-diamine et composition pharmaceutique pour la prévention ou le traitement du cancer contenant celui-ci comme ingrédient actif | |
WO2016006974A2 (fr) | Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation | |
WO2016006975A2 (fr) | Nouveaux dérivés imidazotriazinone ou imidazopyrazinone et leur utilisation | |
WO2011049274A1 (fr) | Dérivés d'imidazole et compositions pour le traitement d'un mélanome | |
WO2023195773A1 (fr) | Dérivé hétéroaryle et son utilisation | |
WO2021201576A1 (fr) | Composé dérivé de benzothiazole | |
WO2022139304A1 (fr) | Nouveau composé dérivé de quinazoline en tant qu'inhibiteur de sos1, et son utilisation | |
WO2022225238A1 (fr) | Composé dérivé d'hétéroaryle et son utilisation | |
WO2010032986A2 (fr) | Nouveaux dérivés de 5-(4-aminophenyl)-isoquinoline, leurs sels pharmaceutiquement acceptables, procédé de production associé et composition contenant les dérivés comme principe actif pour la prophylaxie et le traitement d'états pathologiques induits par l'hyperactivité de la kinase raf | |
AU2019344240B2 (en) | Novel thiazole derivatives and pharmaceutically acceptable salts thereof | |
WO2020263058A1 (fr) | Dérivé d'aminocyanopyridine et son utilisation | |
WO2021040422A1 (fr) | Nouveau dérivé de pyrimido[4,5-d]pyrimidine-2-one ayant une activité inhibitrice de protéine kinase | |
EP3166945A2 (fr) | Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation | |
WO2021086077A1 (fr) | Dérivé d'isoquinolinone, son procédé de préparation et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie associée à la poly(adp-ribose) polymérase-1 (parp-1) | |
WO2019039905A1 (fr) | Nouvel inhibiteur de la tryptophane hydroxylase et composition pharmaceutique le comprenant | |
WO2020106059A1 (fr) | Nouveau composé tricyclique en tant qu'inhibiteur d'irak4 | |
WO2022270977A1 (fr) | Nouveau composé dérivé de pyridine en tant qu'inhibiteur de ron |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18798751 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 18798751 Country of ref document: EP Kind code of ref document: A1 |