JP7526673B2 - がんを治療するためのｈｐｋ１阻害剤としてのｎ－（フェニル）－２－（フェニル）ピリミジン－４－カルボキサミド誘導体及び関連化合物 - Google Patents
がんを治療するためのｈｐｋ１阻害剤としてのｎ－（フェニル）－２－（フェニル）ピリミジン－４－カルボキサミド誘導体及び関連化合物 Download PDFInfo
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- JP7526673B2 JP7526673B2 JP2020566534A JP2020566534A JP7526673B2 JP 7526673 B2 JP7526673 B2 JP 7526673B2 JP 2020566534 A JP2020566534 A JP 2020566534A JP 2020566534 A JP2020566534 A JP 2020566534A JP 7526673 B2 JP7526673 B2 JP 7526673B2
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- 150000001875 compounds Chemical class 0.000 title claims description 136
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 title claims description 25
- 206010028980 Neoplasm Diseases 0.000 title claims description 7
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 title claims description 5
- 201000011510 cancer Diseases 0.000 title claims description 5
- XVLYIDSQDWSVHR-UHFFFAOYSA-N N,2-diphenylpyrimidine-4-carboxamide Chemical class C1(=CC=CC=C1)NC(=O)C1=NC(=NC=C1)C1=CC=CC=C1 XVLYIDSQDWSVHR-UHFFFAOYSA-N 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 927
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 524
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 522
- 125000001424 substituent group Chemical group 0.000 claims description 507
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 500
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 494
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 451
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 386
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 377
- 125000003118 aryl group Chemical group 0.000 claims description 368
- 125000002947 alkylene group Chemical group 0.000 claims description 346
- 229910052799 carbon Inorganic materials 0.000 claims description 271
- 229910052739 hydrogen Inorganic materials 0.000 claims description 248
- -1 aminosulfonylamino Chemical group 0.000 claims description 243
- 125000005843 halogen group Chemical group 0.000 claims description 194
- 125000004429 atom Chemical group 0.000 claims description 123
- 150000003839 salts Chemical class 0.000 claims description 119
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 111
- 229910052717 sulfur Inorganic materials 0.000 claims description 93
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 80
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 80
- 125000003545 alkoxy group Chemical group 0.000 claims description 79
- 125000004432 carbon atom Chemical group C* 0.000 claims description 76
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 75
- 229910052805 deuterium Inorganic materials 0.000 claims description 69
- 229910052760 oxygen Inorganic materials 0.000 claims description 65
- 125000005842 heteroatom Chemical group 0.000 claims description 64
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 58
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 55
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 52
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 47
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 47
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 45
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 40
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 40
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 12
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 10
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 101000869592 Daucus carota Major allergen Dau c 1 Proteins 0.000 claims description 7
- 101000650136 Homo sapiens WAS/WASL-interacting protein family member 3 Proteins 0.000 claims description 7
- 102100027539 WAS/WASL-interacting protein family member 3 Human genes 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 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 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 5
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 5
- 125000005983 2,5-diazabicyclo[2.2.1]heptan-2-yl group Chemical group 0.000 claims description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 5
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 5
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- AASCKKABVVRGPP-UHFFFAOYSA-N 2-(2-fluoro-6-methoxyphenyl)-N-(2-piperidin-4-ylphenyl)pyrimidine-4-carboxamide Chemical compound FC1=C(C(=CC=C1)OC)C1=NC=CC(=N1)C(=O)NC1=C(C=CC=C1)C1CCNCC1 AASCKKABVVRGPP-UHFFFAOYSA-N 0.000 claims description 2
- NMDDKDJYFSZOAT-UHFFFAOYSA-N 2-(2-fluoro-6-methoxyphenyl)-N-[5-fluoro-2-(2-pyridin-2-ylpyrrolidin-1-yl)phenyl]pyrimidine-4-carboxamide Chemical compound FC=1C=CC(=C(C=1)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F)N1C(CCC1)C1=NC=CC=C1 NMDDKDJYFSZOAT-UHFFFAOYSA-N 0.000 claims description 2
- LEIMWMGQPLLTEJ-CQSZACIVSA-N 2-(2-fluoro-6-methoxyphenyl)-N-[5-fluoro-2-[(2R)-2-methylpiperazin-1-yl]phenyl]pyrimidine-4-carboxamide Chemical compound C1=C(F)C=CC(=C1NC(=O)C1=CC=NC(=N1)C1=C(F)C=CC=C1OC)N1[C@@H](CNCC1)C LEIMWMGQPLLTEJ-CQSZACIVSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- RNXDYGITDFPZQI-TYKWCNGQSA-N C=1(C(=NN(C=1C)C)C)C1=CC=C(NC(=O)C2=CC=NC(=N2)C2=C(OC)C=CC=C2F)C([C@H]2CC[C@@H](N)CC2)=C1 Chemical compound C=1(C(=NN(C=1C)C)C)C1=CC=C(NC(=O)C2=CC=NC(=N2)C2=C(OC)C=CC=C2F)C([C@H]2CC[C@@H](N)CC2)=C1 RNXDYGITDFPZQI-TYKWCNGQSA-N 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- CICYHHIRLJBKTE-UHFFFAOYSA-N N-[2-(3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrol-1-yl)-5-fluorophenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COC1=CC=CC(F)=C1C1=NC(=CC=N1)C(=O)NC1=C(C=CC(F)=C1)N1CCC2CNCC12 CICYHHIRLJBKTE-UHFFFAOYSA-N 0.000 claims description 2
- GQAGJQNVOPGUCQ-UHFFFAOYSA-N N-[2-(3-aminocyclohexyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N(C1=C(C2CC(CCC2)N)C=CC=C1)C(=O)C1=CC=NC(=N1)C1=C(OC)C=CC=C1F GQAGJQNVOPGUCQ-UHFFFAOYSA-N 0.000 claims description 2
- LLFCXYBVJBKXHH-UHFFFAOYSA-N N-[2-(3-aminocyclopentyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N(C1=C(C2CCC(N)C2)C=CC=C1)C(=O)C1=CC=NC(=N1)C1=C(OC)C=CC=C1F LLFCXYBVJBKXHH-UHFFFAOYSA-N 0.000 claims description 2
- WTMHDVVBBKONHX-HZPDHXFCSA-N N-[2-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-(hydroxymethyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound [C@H]12N(C[C@H](NC1)C2)C1=C(C=C(C=C1)CO)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F WTMHDVVBBKONHX-HZPDHXFCSA-N 0.000 claims description 2
- KDAAWCZNTXBHPP-QZTJIDSGSA-N N-[2-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-3-(1-methylpyrazol-4-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound [C@H]12N(C[C@H](NC1)C2)C1=C(C=C(C=C1C=1C=NN(C=1)C)F)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F KDAAWCZNTXBHPP-QZTJIDSGSA-N 0.000 claims description 2
- YOVUFANMIRCCQZ-RTBURBONSA-N N-[2-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-3-pyridin-3-ylphenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound [C@H]12N(C[C@H](NC1)C2)C1=C(C=C(C=C1C=1C=NC=CC=1)F)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F YOVUFANMIRCCQZ-RTBURBONSA-N 0.000 claims description 2
- JKHBVOCOHYSWTQ-HUUCEWRRSA-N N-[2-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluorophenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound [C@H]12N(C[C@H](NC1)C2)C1=C(C=C(C=C1)F)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F JKHBVOCOHYSWTQ-HUUCEWRRSA-N 0.000 claims description 2
- UTYUODSGWVOIFI-HUUCEWRRSA-N N-[2-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-methoxyphenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound [C@H]12N(C[C@H](NC1)C2)C1=C(C=C(C=C1)OC)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F UTYUODSGWVOIFI-HUUCEWRRSA-N 0.000 claims description 2
- VFYLBKWAGCOTCH-IAGOWNOFSA-N N-[2-[(1R,4R)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluorophenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound C(C)N1[C@H]2CN([C@@H](C1)C2)C1=C(C=C(C=C1)F)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F VFYLBKWAGCOTCH-IAGOWNOFSA-N 0.000 claims description 2
- QIDMUDUZDJKNEX-PMACEKPBSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-(1,3,5-trimethylpyrazol-4-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1ccc(cc1N1C[C@@H]2C[C@H]1CN2)-c1c(C)nn(C)c1C QIDMUDUZDJKNEX-PMACEKPBSA-N 0.000 claims description 2
- VCZPJHYQIPIKSV-PMACEKPBSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-(2-methylpyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1ccc(cc1N1C[C@@H]2C[C@H]1CN2)-c1cccnc1C VCZPJHYQIPIKSV-PMACEKPBSA-N 0.000 claims description 2
- DSDYWUYEEWMDFK-OALUTQOASA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-(4-methoxypyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1ccncc1-c1ccc(NC(=O)c2ccnc(n2)-c2c(F)cccc2OC)c(c1)N1C[C@@H]2C[C@H]1CN2 DSDYWUYEEWMDFK-OALUTQOASA-N 0.000 claims description 2
- JEHNXRAWWCPZSM-IHPCNDPISA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-[(2S)-2-(methoxymethyl)azetidin-1-yl]phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COC[C@@H]1CCN1c1ccc(NC(=O)c2ccnc(n2)-c2c(F)cccc2OC)c(c1)N1C[C@@H]2C[C@H]1CN2 JEHNXRAWWCPZSM-IHPCNDPISA-N 0.000 claims description 2
- UZLJNVXUUAUUCL-ROUUACIJSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-(1-methyl-6-oxopyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(cc1N1C[C@@H]2C[C@H]1CN2)-c1ccc(=O)n(C)c1 UZLJNVXUUAUUCL-ROUUACIJSA-N 0.000 claims description 2
- IVCZPZNMHCJCCD-IRXDYDNUSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-(1-methylpyrazol-4-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(cc1N1C[C@@H]2C[C@H]1CN2)-c1cnn(C)c1 IVCZPZNMHCJCCD-IRXDYDNUSA-N 0.000 claims description 2
- JBFWLYUTIKICBY-ROUUACIJSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-(2-methylpyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(cc1N1C[C@@H]2C[C@H]1CN2)-c1cccnc1C JBFWLYUTIKICBY-ROUUACIJSA-N 0.000 claims description 2
- UIXZBVNKVGAKSX-GJZGRUSLSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-(hydroxymethyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(CO)cc1N1C[C@@H]2C[C@H]1CN2 UIXZBVNKVGAKSX-GJZGRUSLSA-N 0.000 claims description 2
- YVDUQPDPKGEWFB-OALUTQOASA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-(morpholin-4-ylmethyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(CN2CCOCC2)cc1N1C[C@@H]2C[C@H]1CN2 YVDUQPDPKGEWFB-OALUTQOASA-N 0.000 claims description 2
- YVSYOIRMGSWDKV-OALUTQOASA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-[6-(hydroxymethyl)pyridin-3-yl]phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(cc1N1C[C@@H]2C[C@H]1CN2)-c1ccc(CO)nc1 YVSYOIRMGSWDKV-OALUTQOASA-N 0.000 claims description 2
- CDXQAYIDSWLSDP-ROUUACIJSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-[6-(methylcarbamoyl)pyridin-3-yl]phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound CNC(=O)c1ccc(cn1)-c1cc(N2C[C@@H]3C[C@H]2CN3)c(NC(=O)c2ccnc(n2)-c2c(F)cccc2OC)cc1F CDXQAYIDSWLSDP-ROUUACIJSA-N 0.000 claims description 2
- DDNGJFFPOPCHAZ-IRXDYDNUSA-N N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-fluoro-4-morpholin-4-ylphenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound COc1cccc(F)c1-c1nccc(n1)C(=O)Nc1cc(F)c(cc1N1C[C@@H]2C[C@H]1CN2)N1CCOCC1 DDNGJFFPOPCHAZ-IRXDYDNUSA-N 0.000 claims description 2
- JJXNJDIRWJNGBX-OAHLLOKOSA-N N-[2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-5-fluorophenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N(C1=C(N2CCC[C@@H]2CN)C=CC(F)=C1)C(=O)C1=CC=NC(=N1)C1=C(F)C=CC=C1OC JJXNJDIRWJNGBX-OAHLLOKOSA-N 0.000 claims description 2
- HGFPJAGQCIFATM-OAQYLSRUSA-N N-[2-[(2R)-2-(cyanomethyl)morpholin-4-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound C1(C=2C=NC=CC=2C#N)=CC=C(NC(=O)C2=CC=NC(=N2)C2=C(F)C=CC=C2OC)C(N2C[C@@H](CC#N)OCC2)=C1 HGFPJAGQCIFATM-OAQYLSRUSA-N 0.000 claims description 2
- NRYRSQRRSBLVER-IRXDYDNUSA-N N-[2-[(2S,4S)-4-(dimethylamino)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-fluorophenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound C1=C(F)C=CC(=C1NC(=O)C1=CC=NC(=N1)C1=C(F)C=CC=C1OC)N1C[C@@H](N(C)C)C[C@H]1CO NRYRSQRRSBLVER-IRXDYDNUSA-N 0.000 claims description 2
- WXKLVVXNBFIYSG-DCFHFQCYSA-N N-[2-[(2S,4S)-4-amino-2-(1-hydroxycyclopropyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F)C1(CC1)O WXKLVVXNBFIYSG-DCFHFQCYSA-N 0.000 claims description 2
- YTYIKQGGIQKXKW-DCFHFQCYSA-N N-[2-[(2S,4S)-4-amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F)C(C)(C)O YTYIKQGGIQKXKW-DCFHFQCYSA-N 0.000 claims description 2
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- SXTCCWXLNUBUGV-PMACEKPBSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(2-cyano-6-fluorophenyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound FC1=C(C2=CC=C(NC(=O)C3=CC=NC(=N3)C3=C(F)C=CC=C3OC)C(N3C[C@@H](N)C[C@H]3CO)=C2)C(C#N)=CC=C1 SXTCCWXLNUBUGV-PMACEKPBSA-N 0.000 claims description 2
- BLLJUCXNHUVEHL-PMACEKPBSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(2-methylpyridin-3-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound C=1(C=CC=NC=1C)C1=CC=C(NC(=O)C2=CC=NC(=N2)C2=C(F)C=CC=C2OC)C(N2C[C@@H](N)C[C@H]2CO)=C1 BLLJUCXNHUVEHL-PMACEKPBSA-N 0.000 claims description 2
- HENRITOGWFFGGA-PMACEKPBSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(3-cyanopyridin-2-yl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C1=NC=CC=C1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F)CO HENRITOGWFFGGA-PMACEKPBSA-N 0.000 claims description 2
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- SOVOQANEIZCLPU-SFTDATJTSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-(2-fluoro-6-methylphenyl)pyrimidine-4-carboxamide Chemical compound C(#N)C1=C(C2=CC=C(NC(=O)C3=CC=NC(=N3)C3=C(C)C=CC=C3F)C(N3[C@@H](C[C@H](N)C3)CO)=C2)C=NC=C1 SOVOQANEIZCLPU-SFTDATJTSA-N 0.000 claims description 2
- YAOFYZWYGQFFGQ-OALUTQOASA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-(3,6-difluoro-2-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound C1(C#N)=C(C2=CC=C(NC(=O)C3=CC=NC(=N3)C3=C(OC)C(F)=CC=C3F)C(N3C[C@@H](N)C[C@H]3CO)=C2)C=NC=C1 YAOFYZWYGQFFGQ-OALUTQOASA-N 0.000 claims description 2
- GNAQOVDYXBQJML-PMACEKPBSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-(3,6-difluoro-2-methylphenyl)pyrimidine-4-carboxamide Chemical compound C(#N)C1=C(C2=CC=C(NC(=O)C3=CC=NC(=N3)C3=C(C)C(F)=CC=C3F)C(N3[C@@H](C[C@H](N)C3)CO)=C2)C=NC=C1 GNAQOVDYXBQJML-PMACEKPBSA-N 0.000 claims description 2
- SEKQICVALVTKMV-LAYNNCTGSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-[2,3-difluoro-6-(trideuteriomethoxy)phenyl]pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C(=CC=C1OC([2H])([2H])[2H])F)F)CO SEKQICVALVTKMV-LAYNNCTGSA-N 0.000 claims description 2
- FMVORWLTJBNIRP-OALUTQOASA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-[2-(difluoromethoxy)-6-fluorophenyl]pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1F)OC(F)F)CO FMVORWLTJBNIRP-OALUTQOASA-N 0.000 claims description 2
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- YAOFYZWYGQFFGQ-LAYNNCTGSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-[3,6-difluoro-2-(trideuteriomethoxy)phenyl]pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C(=CC=C1F)F)OC([2H])([2H])[2H])CO YAOFYZWYGQFFGQ-LAYNNCTGSA-N 0.000 claims description 2
- OBXZCGSMSIDKGN-JDNSAJSRSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-[3-cyano-2-fluoro-6-(trideuteriomethoxy)phenyl]pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C(=CC=C1OC([2H])([2H])[2H])C#N)F)CO OBXZCGSMSIDKGN-JDNSAJSRSA-N 0.000 claims description 2
- XCAXLCSQKKQKHA-QJPPTZNUSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyanopyridin-3-yl)phenyl]-2-[3-deuterio-6-fluoro-2-(trideuteriomethoxy)phenyl]pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)C=1C=NC=CC=1C#N)NC(=O)C1=NC(=NC=C1)C1=C(C=CC(=C1OC([2H])([2H])[2H])[2H])F)CO XCAXLCSQKKQKHA-QJPPTZNUSA-N 0.000 claims description 2
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- ATUJAUVLSRXUKR-GJZGRUSLSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-fluorophenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound C1(=CC=C(C=C1N1[C@@H](C[C@H](N)C1)CO)F)NC(=O)C1=CC=NC(=N1)C1=C(OC)C=CC=C1F ATUJAUVLSRXUKR-GJZGRUSLSA-N 0.000 claims description 2
- IOHPKJPPERILGU-GJZGRUSLSA-N N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-methylsulfonylphenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide Chemical compound N[C@H]1C[C@H](N(C1)C1=C(C=CC(=C1)S(=O)(=O)C)NC(=O)C1=NC(=NC=C1)C1=C(C=CC=C1OC)F)CO IOHPKJPPERILGU-GJZGRUSLSA-N 0.000 claims description 2
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- A61K31/33—Heterocyclic compounds
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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
- C07D487/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862632702P | 2018-02-20 | 2018-02-20 | |
| US62/632,702 | 2018-02-20 | ||
| US201862672772P | 2018-05-17 | 2018-05-17 | |
| US62/672,772 | 2018-05-17 | ||
| US201862750371P | 2018-10-25 | 2018-10-25 | |
| US62/750,371 | 2018-10-25 | ||
| PCT/US2019/018608 WO2019164846A1 (en) | 2018-02-20 | 2019-02-19 | N-(phenyl)-2-(phenyl)pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| JP2021515033A JP2021515033A (ja) | 2021-06-17 |
| JPWO2019164846A5 JPWO2019164846A5 (https=) | 2022-02-22 |
| JP2021515033A5 JP2021515033A5 (https=) | 2022-02-22 |
| JP7526673B2 true JP7526673B2 (ja) | 2024-08-01 |
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